|
Compound is evaluated for the inhibition of porcine plasma Angiotensin I converting enzyme
|
Sus scrofa
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of a ketomethylene analogue of a tripeptide inhibitor of angiotensin converting enzyme.
Year : 1980
Volume : 23
Issue : 12
First Page : 1392
Last Page : 1398
Authors : Almquist RG, Chao WR, Ellis ME, Johnson HL.
Abstract : An analogue of a tripeptide inhibitor of angiotensin converting enzyme, Bz-Phe-Gly-Pro, has been synthesized in which the amide bond connecting phenylalanine and glycine has been replaced by a ketomethylene group. This nonpeptide analogue, 20, shows more potent converting enzyme inhibiting activity, I50 = 0.07 microM, than Bz-Phe-Gly-Pro, I50 = 9.4 microM, or than the orally active D-3-mercapto-2-methylpropanoyl-L-proline (captopril, 1), I50 = 0.30 microM. Compound 20 has a Ki of 1.06 X 10(-7) and either competitive or noncompetitive enzyme kinetics depending on what substrate is used in the converting enzyme assay. In tests for inhibition of angiotensin I induced contractions in the guinea pig ileum, 20 has one-tenth the activity of 1.
|
Compound was evaluated for inhibition of porcine plasma Angiotensin I converting enzyme by using fluorometric assay
|
Sus scrofa
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of pentapeptide analogues of the potent angiotensin converting enzyme inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline.
Year : 1985
Volume : 28
Issue : 8
First Page : 1062
Last Page : 1066
Authors : Almquist RG, Jennings-White C, Chao WR, Steeger T, Wheeler K, Rogers J, Mitoma C.
Abstract : Two pentapeptide analogues of the ketomethylene-containing angiotensin converting enzyme (ACE) inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline (1) were synthesized and evaluated as ACE inhibitors and antihypertensive agents. Compounds 14 and 15 were very potent ACE inhibitors with I50 values of 7.0 and 3.0 nM, respectively, compared to an I50 value of 70 nM for 1. Neither 14 nor 15 showed significant blood pressure lowering activity in renal hypertensive rats. Investigations conducted on a tritiated analogue of 14 showed that 70% of an oral dose of this compound is absorbed but is rapidly excreted from the blood with a half life of 24 min. Thin-layer chromatography of bile and urine contents in rats given tritiated 14 orally showed that it is excreted in greater than 90% unchanged form. This implies that a ketomethylene linkage can stabilize peptide amide linkages adjacent to it to peptidase degradation.
|
In vitro inhibition of Angiotensin I converting enzyme activity at pH 8.5 in rabbit lung
|
Oryctolagus cuniculus
|
17.0
nM
|
|
Journal : J. Med. Chem.
Title : Angiotensin-converting enzyme inhibitors: new orally active 1,4-thiazepine-2,5-diones, 1,4-thiazine-2,5-diones, and 1,4-benzothiazepine-2,5-diones possessing antihypertensive activity.
Year : 1986
Volume : 29
Issue : 5
First Page : 784
Last Page : 796
Authors : Skiles JW, Suh JT, Williams BE, Menard PR, Barton JN, Loev B, Jones H, Neiss ES, Schwab A, Mann WS.
Abstract : The preparation of a series of 1,4-thiazepine-2,5-diones, 1,4-thiazine-2,5-diones, and 1,4-benzothiazepine-2,5-diones and their ability in inhibiting the activity of angiotensin-converting enzyme (ACE) in vitro and in vivo were examined. These compounds are assumed to act as prodrugs since they undergo rapid ring-opening reactions to give the corresponding biologically active free SH compounds when incubated with rat plasma or when treated with aqueous 0.1 N HCl or phosphate buffer (pH 7.4). The thiazepines 23-25 and 30 are potent inhibitors of ACE when administered po to rats and are comparable in potency to captopril (1). The most active thiazines in rats, po, were 42 and 45. Of the benzothiazepines studied, 22a was the most active in inhibiting ACE in the conscious normotensive rat, ID50 = 0.15 mg/kg, po. The acute antihypertensive effects of oral administration of a number of these compounds on mean arterial pressure and heart rate were studied in spontaneously hypertensive rats (SHR) maintained on a sodium-deficient diet.
|
In vitro inhibition of angiotensin I converting enzyme in rabbit lung with hippuryl-histidyl-leucine as substrate
|
Oryctolagus cuniculus
|
23.0
nM
|
|
Journal : J. Med. Chem.
Title : (Phosphinyloxy)acyl amino acid inhibitors of angiotensin converting enzyme (ACE). 1. Discovery of (S)-1-[6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L -proline a novel orally active inhibitor of ACE.
Year : 1988
Volume : 31
Issue : 1
First Page : 204
Last Page : 212
Authors : Karanewsky DS, Badia MC, Cushman DW, DeForrest JM, Dejneka T, Loots MJ, Perri MG, Petrillo EW, Powell JR.
Abstract : The synthesis of a series of orally active, phosphinyloxyacyl proline inhibitors of angiotensin converting enzyme (ACE) is described. The in vitro and in vivo ACE inhibitory activities are reported for each compound. The structure-activity relationship for this series of compounds in relation to the carboxyalkyl dipeptide ACE inhibitors as well as other types of hydroxyphosphinyl-containing ACE inhibitors (e.g., the corresponding nitrogen and carbon isosteres) is discussed. Within an isosteric series of phosphorus-containing inhibitors based on the lysylproline terminal dipeptide sequence, only the phosphonates (oxygen isosteres) show a high level of oral activity. Optimum potency and oral activity in the phosphonate series occurs with the (phenylbutyl)- and n-hexylphosphonate side chains. An aminobutyl side chain in the P1' residue is an absolute requirement for full expression of oral activity. The most potent of these compounds, 8b (SQ 29,852), has intravenous and oral activities superior in potency to those of captopril in the normotensive rat.
|
In vitro inhibitory activity against Angiotensin I converting enzyme in rabbit lung, using hippuryl-histidyl-leucine as substrate
|
Oryctolagus cuniculus
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Angiotensin-converting enzyme inhibitors: importance of the amide carbonyl of mercaptoacyl amino acids for hydrogen bonding to the enzyme.
Year : 1982
Volume : 25
Issue : 3
First Page : 250
Last Page : 258
Authors : Condon ME, Petrillo EW, Ryono DE, Reid JA, Neubeck R, Puar M, Heikes JE, Sabo EF, Losee KA, Cushman DW, Ondetti MA.
Abstract : A series of mercaptoacyl amino acids and related compounds was synthesized and evaluated for inhibition of angiotensin-converting enzyme (ACE) in order to determine the nature and importance of the putative interaction between ACE and the amide moiety of inhibitors such as captopril (3-mercapto-2-methylpropanoyl-L-proline). It was concluded that the interaction involves a hydrogen bond from a donor site on ACE to the oxygen of the amide carbonyl. Compounds in which the amide moiety is replaced by other groups (ester, ketone, sulfonamide) capable of accepting a hydrogen bond are effective inhibitors, but compounds in which only the geometrical features of the amide are retained are ineffective inhibitors. The presence of an NH group is not necessary for effective inhibition. The activity of a series of mercaptoacyl cycloalkyl carboxylic acids parallels the activity of the isosteric series of mercaptoacyl imino acids.
|
Tested for inhibitory concentration against Angiotensin converting enzyme (ACE) obtained from rabbit lung acetone powder extract
|
Oryctolagus cuniculus
|
0.005
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : K-13 and of4949: Evaluation of key partial structures and pharmacophore delineation
Year : 1993
Volume : 3
Issue : 2
First Page : 245
Last Page : 250
Authors : Boger DL, Yohannes D
|
Compound was tested for its inhibitory activity against Angiotensin I converting enzyme
|
Oryctolagus cuniculus
|
13.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Probing the importance of spacial and conformational domains in captopril analogs for angiotensin converting enzyme activity.
Year : 1998
Volume : 8
Issue : 16
First Page : 2123
Last Page : 2128
Authors : Hanessian S, Reinhold U, Saulnier M, Claridge S.
Abstract : A new synthesis of 4,5-methano-L-prolines and the enzymatic activity of the corresponding N-(3-mercapto-2-R-methyl-propionyl) analogs as inhibitors of angiotensin converting enzyme are described.
|
Evaluation of in vitro inhibitory activity against Angiotensin I converting enzyme
|
Oryctolagus cuniculus
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : New alpha-thiol dipeptide dual inhibitors of angiotensin-I converting enzyme and neutral endopeptidase EC 3.4.24.11.
Year : 1995
Volume : 38
Issue : 26
First Page : 5023
Last Page : 5030
Authors : Fink CA, Qiao Y, Berry CJ, Sakane Y, Ghai RD, Trapani AJ.
Abstract : Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I converting enzyme, have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. A novel series of alpha-thio dipeptides containing central cyclic non-natural amino acids were prepared and were evaluated for their ability to inhibit these two metallopeptidases in vitro and in vivo. Most of these compounds were found to be excellent dual inhibitors of ACE and NEP in vitro and several were also found to inhibit angiotensin-I (AI) pressor response in conscious rats when given by intravenous administration. Compound 6n, one of our most potent dual inhibitors in vitro, was found to be more efficacious than captopril in the AI pressor experiment when administered orally to conscious rats. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. The structure-activity relationships and biological activity of these dual inhibitors will be discussed.
|
In vitro 50% inhibition of Angiotensin I converting enzyme
|
Oryctolagus cuniculus
|
22.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological activity of angiotensin converting enzyme inhibitors: N-(mercaptoacyl)-4-substituted-(S)-prolines.
Year : 1988
Volume : 31
Issue : 4
First Page : 875
Last Page : 885
Authors : Smith EM, Swiss GF, Neustadt BR, Gold EH, Sommer JA, Brown AD, Chiu PJ, Moran R, Sybertz EJ, Baum T.
Abstract : The synthesis of a series of N-(mercaptoacyl)-4-substituted-(S)-prolines (2 and 3) is described. These compounds were evaluated in vitro for inhibition of angiotensin-converting enzyme (ACE), and selected compounds were evaluated in vivo for ACE inhibition. The most potent compounds in vitro are 108, 109, 111, 114, and 116, having relative potencies of 1.0, 1.0, 1.3, 1.1, and 2.6 as compared to the potency of captopril. The most potent compounds in vivo intravenously are 108, 111, 114, 116, 117, and 97.
|
In vitro inhibition of Angiotensin I converting enzyme
|
Oryctolagus cuniculus
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : Angiotensin converting enzyme inhibitors: N-substituted monocyclic and bicyclic amino acid derivatives.
Year : 1983
Volume : 26
Issue : 9
First Page : 1267
Last Page : 1277
Authors : Stanton JL, Gruenfeld N, Babiarz JE, Ackerman MH, Friedmann RC, Yuan AM, Macchia W.
Abstract : The synthesis of N-(3-mercaptopropionyl)-N-arylglycines (14a-x),- N-arylalanines (15a,b),-N-cycloalkylglycines (16a-k), and -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids (17a-d), -1,2,3,4-tetrahydroquinoline-2-carboxylic acids (18a-f), and -indoline-2-carboxylic acids (19a-k) is described. In vitro inhibition of angiotensin converting enzyme (ACE) is reported for each compound, and the structure--activity relationship for each series is discussed. The in vivo inhibition of ACE and antihypertensive effects of representative compounds from each series are discussed. The most potent compound, 19d, had an in vitro ACE IC50 of 2.6 X 10(-9) M and lowered blood pressure in spontaneous hypertensive rats 85 mm at a dose of 10 mg/kg po.
|
In vitro inhibition of angiotensin I converting enzyme (ACE)
|
Oryctolagus cuniculus
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : Angiotensin converting enzyme inhibitors: 1-glutarylindoline-2-carboxylic acids derivatives.
Year : 1983
Volume : 26
Issue : 9
First Page : 1277
Last Page : 1282
Authors : Gruenfeld N, Stanton JL, Yuan AM, Ebetino FH, Browne LJ, Gude C, Huebner CF.
Abstract : The preparation of a series of 1-glutarylindoline-2(S)-carboxylic acid derivatives, 6a-v and 21a-c, is described. The above compounds were tested for inhibition of angiotensin converting enzyme. The structure-activity relationship of the series is also discussed. Compound 6u, the most potent member of the series, had an in vitro IC50 of 4.8 X 10(-9) M. Compound 6v, an ethyl ester of 6u, lowered blood pressure 70 mm in spontaneous hypertensive rats at an oral dose of 30 mg/kg.
|
In vitro inhibition of rabbit lung Angiotensin I converting enzyme (ACE) using Hippuryl-His-Leu as substrate
|
Oryctolagus cuniculus
|
23.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Mercaptoacyl dipeptides as dual inhibitors of angiotensin-converting enzyme and neutral endopeptidase. Preliminary structure-activity studies
Year : 1994
Volume : 4
Issue : 15
First Page : 1783
Last Page : 1788
Authors : Delaney NG, Barrish JC, Neubeck R, Natarajan S, Cohen M, Rovnyak GC, Huber G, Murugesan N, Girotra R, Sieber-McMaster E, Robl JA, Asaad MM, Cheung HS, Bird J, Waldron T, Petrillo EW
|
In vitro inhibitory activity against Angiotensin I converting enzyme
|
Oryctolagus cuniculus
|
2.7e-05
nM
|
|
Journal : J. Med. Chem.
Title : Angiotensin converting enzyme inhibitors. (Mercaptoaroyl)amino acids.
Year : 1985
Volume : 28
Issue : 3
First Page : 328
Last Page : 332
Authors : Menard PR, Suh JT, Jones H, Loev B, Neiss ES, Wilde J, Schwab A, Mann WS.
Abstract : A series of (mercaptoaroyl)amino acids and related compounds was synthesized and tested for ability to inhibit angiotensin converting enzyme (ACE). The most active compound was N-(3-chloro-2-mercaptobenzoyl)-N-cyclopentylglycine, having an in vitro I50 = 0.28 microM. Substitution of the aromatic 3-position by small polar groups enhanced ACE inhibitory activity, whereas bulky groups diminished it. Alteration of the beta relationship between the mercaptan and amide carbonyl or masking of the thiol by acylation reduced activity. Replacement of the thiol by nitro, hydroxy, or carboxy gave compounds lacking ACE inhibitory activity.
|
In vitro inhibitory activity against rabbit lung Angiotensin I converting enzyme
|
Oryctolagus cuniculus
|
23.0
nM
|
|
In vitro inhibitory activity against rabbit lung Angiotensin I converting enzyme
|
Oryctolagus cuniculus
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : Angiotensin-converting enzyme inhibitors. New orally active antihypertensive (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycine derivatives.
Year : 1985
Volume : 28
Issue : 1
First Page : 57
Last Page : 66
Authors : Suh JT, Skiles JW, Williams BE, Youssefyeh RD, Jones H, Loev B, Neiss ES, Schwab A, Mann WS, Khandwala A.
Abstract : A variety of N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycine derivatives was synthesized and their ability in inhibiting the activity of angiotensin-converting enzyme (ACE) was examined in vitro and in vivo. The acylthio derivatives prepared are assumed to act as prodrugs since they are much less active than the corresponding free SH compounds in vitro and can be expected to act in vivo only after conversion to the free sulfhydryl compounds. A number of these compounds are potent ACE inhibitors that lowered blood pressure in Na-deficient, conscious spontaneously hypertensive rats (SHR), a high renin model. One of the most active members of the series was (S)-N-cyclopentyl-N-[3-[(2,2-dimethyl-1-oxopropyl)thio]-2-methyl-1 -oxopropyl]glycine (REV 3659-(S), pivopril). Structure-activity relationships are discussed.
|
In vitro inhibitory activity against rabbit lung Angiotensin I converting enzyme at pH 8.3
|
Oryctolagus cuniculus
|
17.0
nM
|
|
Journal : J. Med. Chem.
Title : Angiotensin-converting enzyme inhibitors. New orally active antihypertensive (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycine derivatives.
Year : 1985
Volume : 28
Issue : 1
First Page : 57
Last Page : 66
Authors : Suh JT, Skiles JW, Williams BE, Youssefyeh RD, Jones H, Loev B, Neiss ES, Schwab A, Mann WS, Khandwala A.
Abstract : A variety of N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycine derivatives was synthesized and their ability in inhibiting the activity of angiotensin-converting enzyme (ACE) was examined in vitro and in vivo. The acylthio derivatives prepared are assumed to act as prodrugs since they are much less active than the corresponding free SH compounds in vitro and can be expected to act in vivo only after conversion to the free sulfhydryl compounds. A number of these compounds are potent ACE inhibitors that lowered blood pressure in Na-deficient, conscious spontaneously hypertensive rats (SHR), a high renin model. One of the most active members of the series was (S)-N-cyclopentyl-N-[3-[(2,2-dimethyl-1-oxopropyl)thio]-2-methyl-1 -oxopropyl]glycine (REV 3659-(S), pivopril). Structure-activity relationships are discussed.
|
Inhibitory activity towards purified rabbit lung Angiotensin I converting enzyme
|
Oryctolagus cuniculus
|
2.7
nM
|
|
Journal : J. Med. Chem.
Title : (R)-2-(3-mercapto-2(S)-methyl-1-oxo-propoxy)-3-(methylthio)propanoic acid, the first ultra-short-acting angiotensin converting enzyme inhibitor.
Year : 1992
Volume : 35
Issue : 20
First Page : 3718
Last Page : 3720
Authors : Baxter AJ, Carr RD, Eyley SC, Fraser-Rae L, Hallam C, Harper ST, Hurved PA, King SJ, Meghani P.
|
Inhibitory activity against rabbit lung angiotensin-1 converting enzyme
|
Oryctolagus cuniculus
|
1.7
nM
|
|
Journal : J. Med. Chem.
Title : Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines.
Year : 1988
Volume : 31
Issue : 6
First Page : 1148
Last Page : 1160
Authors : Krapcho J, Turk C, Cushman DW, Powell JR, DeForrest JM, Spitzmiller ER, Karanewsky DS, Duggan M, Rovnyak G, Schwartz J.
Abstract : Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.
|
Ability to inhibit Angiotensin I converting enzyme was determined
|
Oryctolagus cuniculus
|
15.0
nM
|
|
Ability to inhibit Angiotensin I converting enzyme was determined
|
Oryctolagus cuniculus
|
23.0
nM
|
|
Journal : J. Med. Chem.
Title : Bicyclic lactam inhibitors of angiotensin converting enzyme.
Year : 1984
Volume : 27
Issue : 6
First Page : 816
Last Page : 818
Authors : Watthey JW, Gavin T, Desai M.
Abstract : Syntheses of the potent angiotensin converting enzyme inhibitor 1-(carboxymethyl)-3-(mercaptomethyl)-2,3,4,5-tetrahydro-1H-1- benzazep in -2-one (4a) and the corresponding eight-membered ring analogue (4b) are described. The influence of ring size on the inhibitory potencies of these substances is discussed.
|
In vitro inhibition of Angiotensin I converting enzyme in rabbit lung
|
Oryctolagus cuniculus
|
18.0
nM
|
|
Journal : J. Med. Chem.
Title : Angiotensin converting enzyme inhibitors. 10. Aryl sulfonamide substituted N-[1-carboxy-3-phenylpropyl]-L-alanyl-L-proline derivatives as novel antihypertensives.
Year : 1990
Volume : 33
Issue : 6
First Page : 1606
Last Page : 1615
Authors : Mencel JJ, Regan JR, Barton J, Menard PR, Bruno JG, Calvo RR, Kornberg BE, Schwab A, Neiss ES, Suh JT.
Abstract : Compounds 1a-g consisting of enalaprilat covalently bonded to aryl sulfonamides, including several known thiazide diuretics, were synthesized and tested for ACE inhibitory and diuretic and overall antihypertensive effects. All compounds were potent ACE inhibitors in vitro, with IC50 = 6.5-85 nM. At 10 mg/kg iv or ip in the rat, 1a-g inhibited the AI pressor response by 76-100%; inhibition declined significantly upon oral dosing. Compounds 1a and 1f at 100 mg/kg ip in the sodium-depleted, spontaneously hypertensive rats reduced blood pressure 28-35% and 41-42%, respectively. Compounds 1a and 1f elicited natriuresis and kaliuresis without accompanying volume increases in the rat; 1c at 25 mg/kg iv induced delayed diuresis. Compound 1f has been chosen for further development.
|
In vivo inhibition of Angiotensin I converting enzyme in rabbit lung after (po) administration of a dose of 10(mg/kg)
|
Oryctolagus cuniculus
|
69.0
%
|
|
Journal : J. Med. Chem.
Title : Angiotensin converting enzyme inhibitors. 10. Aryl sulfonamide substituted N-[1-carboxy-3-phenylpropyl]-L-alanyl-L-proline derivatives as novel antihypertensives.
Year : 1990
Volume : 33
Issue : 6
First Page : 1606
Last Page : 1615
Authors : Mencel JJ, Regan JR, Barton J, Menard PR, Bruno JG, Calvo RR, Kornberg BE, Schwab A, Neiss ES, Suh JT.
Abstract : Compounds 1a-g consisting of enalaprilat covalently bonded to aryl sulfonamides, including several known thiazide diuretics, were synthesized and tested for ACE inhibitory and diuretic and overall antihypertensive effects. All compounds were potent ACE inhibitors in vitro, with IC50 = 6.5-85 nM. At 10 mg/kg iv or ip in the rat, 1a-g inhibited the AI pressor response by 76-100%; inhibition declined significantly upon oral dosing. Compounds 1a and 1f at 100 mg/kg ip in the sodium-depleted, spontaneously hypertensive rats reduced blood pressure 28-35% and 41-42%, respectively. Compounds 1a and 1f elicited natriuresis and kaliuresis without accompanying volume increases in the rat; 1c at 25 mg/kg iv induced delayed diuresis. Compound 1f has been chosen for further development.
|
In vitro inhibitory activity against angiotensin I converting enzyme of rats.
|
None
|
23.0
nM
|
|
Journal : J. Med. Chem.
Title : Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines.
Year : 1988
Volume : 31
Issue : 6
First Page : 1148
Last Page : 1160
Authors : Krapcho J, Turk C, Cushman DW, Powell JR, DeForrest JM, Spitzmiller ER, Karanewsky DS, Duggan M, Rovnyak G, Schwartz J.
Abstract : Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.
|
In vivo inhibitory activity against Angiotensin I converting enzyme was evaluated in renal hypertensive rats
|
None
|
23.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of carboxylic acid replacement analogues of the potent angiotensin converting enzyme inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline.
Year : 1985
Volume : 28
Issue : 8
First Page : 1067
Last Page : 1071
Authors : Almquist RG, Chao WR, Jennings-White C.
Abstract : The carboxylic acid group on the proline of 1 was replaced by a phosphoric acid, a hydroxamic acid, and a tetrazole to give compounds 2-4, respectively. Testing of 2-4 as angiotensin converting enzyme (ACE) inhibitors gave I50 values of 100, 1.6, and 22 microM, respectively, compared to 0.07 microM for 1. A hydroxamic acid derivative of the ketomethylene pentapeptide analogue 18 was then synthesized. This compound, 17, had an ACE I50 of 0.011 microM compared to 0.0076 microM for 18. Oral administration of 10 mg/kg of 17 to renal hypertensive rats had no effect on blood pressure or heart rate.
|
Inhibition of Angiotensin I converting enzyme in normotensive rat
|
Rattus norvegicus
|
0.45
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of ketomethylene-containing nonapeptide analogues of snake venom angiotensin converting enzyme inhibitors.
Year : 1988
Volume : 31
Issue : 3
First Page : 561
Last Page : 567
Authors : Almquist RG, Chao WR, Judd AK, Mitoma C, Rossi DJ, Panasevich RE, Matthews RJ.
Abstract : Two ketomethylene-containing nonapeptide analogues were synthesized to determine if ketomethylene analogues of the nonapeptide venom inhibitors of angiotensin converting enzyme (ACE) would have oral ACE inhibition activity. Both ketomethylene-containing nonapeptides 18 and 19 were potent inhibitors of rabbit lung ACE with I50s of 3.4 and 8.0 nM, respectively, compared to 340 nM for their parent nonapeptide and 450 nM for captopril. Peptide 18 was rapidly cleaved by trypsin, but 19 was reasonably stable to all enzyme degradation systems tested with maximum degradation of 50% by pepsin in 3 h. Both 18 and 19 when given iv to normotensive rats were between 3 and 10 times more potent than captopril in inhibiting an angiotensin I induced blood pressure increase. Peptide 19 showed no ACE inhibition activity in unanesthetized normotensive rats when administered orally at doses of 10 or 100 mg/kg. Experiments were conducted to determine whether 19 is adsorbed from the gastrointestinal track following oral administration. These experiments indicated that 19 is adsorbed. It is concluded that the lack of oral activity of 19 is probably due to its rapid excretion, probably into the bile.
|
Inhibitory activity against Angiotensin I converting enzyme
|
None
|
590.0
nM
|
|
Journal : J. Med. Chem.
Title : Angiotensin converting enzyme inhibitors as antihypertensive agents: 1-[(2-mercaptocycloalkyl)carbonyl]-L-prolines.
Year : 1986
Volume : 29
Issue : 3
First Page : 411
Last Page : 417
Authors : Ciabatti R, Padova G, Bellasio E, Tarzia G, Depaoli A, Battaglia F, Cellentani M, Barone D, Baldoli E.
Abstract : The synthesis of 1-[(2-mercaptocyclopentyl)carbonyl]-L-prolines, 1-[(2-mercaptocyclobutyl)carbonyl]-L-prolines and related benzoyl derivatives as pure isomers is described. The abilities of all the compounds to inhibit angiotensin converting enzyme (ACE) in vitro and in vivo and to lower the systolic blood pressure in renal hypertensive dogs were determined. Three of them, namely 1-[[2-(benzoylthio)cyclopentyl]carbonyl]-L-proline (10f(R,S], 1-[(2-mercaptocyclopentyl)carbonyl]-L-proline (10g(R,S], and 1-[[2-(benzoylthio)cyclobutyl]carbonyl]-L-proline (16f(R,S], were found to be as potent as captopril in reducing blood pressure. The influence of chirality and ring size on the ACE inhibition is described.
|
Inhibition of rat Angiotensin I converting enzyme (ACE), using Hip-Gly-Gly as synthetic substrate.
|
None
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of potent new angiotensin converting enzyme inhibitors containing saturated bicyclic amino acids.
Year : 1987
Volume : 30
Issue : 6
First Page : 992
Last Page : 998
Authors : Blankley CJ, Kaltenbronn JS, DeJohn DE, Werner A, Bennett LR, Bobowski G, Krolls U, Johnson DR, Pearlman WM, Hoefle ML.
Abstract : The synthesis of a series of novel, potent angiotensin converting enzyme (ACE) inhibitors containing saturated bicyclic amino acids in place of proline is described. Octahydroindole-2-carboxylic acid, octahydroisoindole-1-carboxylic acid, and octahydro-3-oxoisoindole-1-carboxylic acid can replace proline in both sulfhydryl and non-sulfhydryl ACE inhibitors to give compounds equipotent to captopril and enalapril both in vitro and in vivo. Structure-activity relationships are discussed. Compound 11a (CI-907, indolapril) has advanced to clinical evaluation.
|
In vitro antihypertensive activity determined by inhibition of angiotensin I converting enzyme
|
None
|
156.0
nM
|
|
Journal : J. Med. Chem.
Title : Antihypertensive agents: angiotensin converting enzyme inhibitors. 1-[3-(Acylthio)-3-aroylpropionyl]-L-prolines.
Year : 1983
Volume : 26
Issue : 3
First Page : 381
Last Page : 394
Authors : McEvoy FJ, Lai FM, Albright JD.
Abstract : A series of 1-[3-(acylthio)-3-aroylpropionyl]-L-proline derivatives was synthesized. A number of these compounds are potent angiotensin converting enzyme (ACE) inhibitors that lowered blood pressure in aorta-coarcted renal hypertensive rats. The most active derivatives are 1-[3(R)-(acetylthio) -3-substituted-benzoyl)-2(S)-methyl-propionyl]-L-prolines with an in vivo activity equivalent to SQ 14,225 (captopril). Structure-activity relationships are discussed. Changes in the configuration of the alpha-methyl group and the S-acetyl group affect the ACE activity. Coupling of 3-(substituted-benzoyl)-2-methylpropionic acids to L-proline via enol lactones is described.
|
Inhibition of Angiotensin I converting enzyme in rat
|
Rattus norvegicus
|
15.0
nM
|
|
Inhibition of Angiotensin I converting enzyme in rat
|
Rattus norvegicus
|
70.0
nM
|
|
Journal : J. Med. Chem.
Title : Angiotensin converting enzyme inhibitors: 1,5-benzothiazepine derivatives.
Year : 1985
Volume : 28
Issue : 10
First Page : 1517
Last Page : 1521
Authors : Slade J, Stanton JL, Ben-David D, Mazzenga GC.
Abstract : The synthesis of chiral 1,5-benzothiazepines 2a-c, 14a-c, 15c, and 16a prepared from cysteine is described. In vitro inhibition of angiotensin converting enzyme (ACE) is reported for each compound. Compound 2c was the most potent in vitro having an IC50 of 2.95 nM. The ester of 2c, i.e. 14c, was found to inhibit the AI pressor response by 75% at a dose of 0.05 mg/kg iv and by 39% at 1.0 mg/kg po. Additionally, 14c lowered blood pressure in the spontaneous hypertensive rat (SHR) by 35 mmHg, at a dose of 10 mg/kg po.
|
In vitro inhibitory activity against Angiotensin I converting enzyme
|
None
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : (Mercaptopropanoyl)indoline-2-carboxylic acids and related compounds as potent angiotensin converting enzyme inhibitors and antihypertensive agents.
Year : 1983
Volume : 26
Issue : 3
First Page : 394
Last Page : 403
Authors : Kim DH, Guinosso CJ, Buzby GC, Herbst DR, McCaully RJ, Wicks TC, Wendt RL.
Abstract : 1-(3-Mercapto-2-methyl-1-oxopropyl)indoline-2-carboxylic acids (7b) and related compounds were synthesized in order to examine their ability to inhibit angiotensin converting enzyme (ACE) and to reduce the systolic blood pressure of spontaneously hypertensive rats (SHR). All four possible stereoisomers of the precursor 1-[3-(benzoylthio)-2-methyl-1-oxopropyl]indoline-2-carboxylic acid (6b) were characterized with absolute stereochemical assignment. The removal of the benzoyl group of the precursor to give 7b was conveniently carried out by treatment with 2-methoxyethylamine. Three of the four stereoisomers of the benzoyl derivative 6 showed in vitro ACE inhibitory activity in the following order: 6b(S,S) greater than 6b(S,R) greater than 6b(R,S). The stereoisomer having the R,R configuration was essentially inactive. The substitution at the C5 of the indoline nucleus with the Et or OMe group caused only marginal changes in the inhibitory activity. The mercaptan 7b(S,S) was the most active ACE inhibitor synthesized in this study, showing in vitro potency 3 times that of captopril. The augmentation of the potency may be due to the increased hydrophobicity of 7b(S,S) compared with captopril and suggests the presence of a hydrophobic pocket at the active site of ACE. When tested in spontaneously hypertensive rats, 7b(S,S) exhibited oral antihypertensive activity 27 times that of captopril. The corresponding benzoyl derivative 6b(S,S) was 24 times as potent as captopril. The thio lactone 10 obtained by cyclization of 7b(S,S) as a potential prodrug was less potent than the parent compound, 7b(S,S), in the ACE inhibitory and antihypertensive tests.
|
Evaluation of plasma inhibition of Angiotensin I converting enzyme activity in conscious rat 1 hour after ia administration at a dose of 10 mg/kg
|
None
|
96.0
%
|
|
Journal : J. Med. Chem.
Title : New alpha-thiol dipeptide dual inhibitors of angiotensin-I converting enzyme and neutral endopeptidase EC 3.4.24.11.
Year : 1995
Volume : 38
Issue : 26
First Page : 5023
Last Page : 5030
Authors : Fink CA, Qiao Y, Berry CJ, Sakane Y, Ghai RD, Trapani AJ.
Abstract : Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I converting enzyme, have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. A novel series of alpha-thio dipeptides containing central cyclic non-natural amino acids were prepared and were evaluated for their ability to inhibit these two metallopeptidases in vitro and in vivo. Most of these compounds were found to be excellent dual inhibitors of ACE and NEP in vitro and several were also found to inhibit angiotensin-I (AI) pressor response in conscious rats when given by intravenous administration. Compound 6n, one of our most potent dual inhibitors in vitro, was found to be more efficacious than captopril in the AI pressor experiment when administered orally to conscious rats. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. The structure-activity relationships and biological activity of these dual inhibitors will be discussed.
|
Evaluation of plasma inhibition of Angiotensin I converting enzyme activity in conscious rat 1 hour after oral administration at a dose of 10 mg/kg
|
None
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : New alpha-thiol dipeptide dual inhibitors of angiotensin-I converting enzyme and neutral endopeptidase EC 3.4.24.11.
Year : 1995
Volume : 38
Issue : 26
First Page : 5023
Last Page : 5030
Authors : Fink CA, Qiao Y, Berry CJ, Sakane Y, Ghai RD, Trapani AJ.
Abstract : Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I converting enzyme, have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. A novel series of alpha-thio dipeptides containing central cyclic non-natural amino acids were prepared and were evaluated for their ability to inhibit these two metallopeptidases in vitro and in vivo. Most of these compounds were found to be excellent dual inhibitors of ACE and NEP in vitro and several were also found to inhibit angiotensin-I (AI) pressor response in conscious rats when given by intravenous administration. Compound 6n, one of our most potent dual inhibitors in vitro, was found to be more efficacious than captopril in the AI pressor experiment when administered orally to conscious rats. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. The structure-activity relationships and biological activity of these dual inhibitors will be discussed.
|
Evaluation of plasma inhibition of Angiotensin I converting enzyme activity in conscious rat 2 hour after oral administration at a dose of 10 mg/kg
|
None
|
78.0
%
|
|
Journal : J. Med. Chem.
Title : New alpha-thiol dipeptide dual inhibitors of angiotensin-I converting enzyme and neutral endopeptidase EC 3.4.24.11.
Year : 1995
Volume : 38
Issue : 26
First Page : 5023
Last Page : 5030
Authors : Fink CA, Qiao Y, Berry CJ, Sakane Y, Ghai RD, Trapani AJ.
Abstract : Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I converting enzyme, have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. A novel series of alpha-thio dipeptides containing central cyclic non-natural amino acids were prepared and were evaluated for their ability to inhibit these two metallopeptidases in vitro and in vivo. Most of these compounds were found to be excellent dual inhibitors of ACE and NEP in vitro and several were also found to inhibit angiotensin-I (AI) pressor response in conscious rats when given by intravenous administration. Compound 6n, one of our most potent dual inhibitors in vitro, was found to be more efficacious than captopril in the AI pressor experiment when administered orally to conscious rats. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. The structure-activity relationships and biological activity of these dual inhibitors will be discussed.
|
Evaluation of plasma inhibition of Angiotensin I converting enzyme activity in conscious rat 2 hours after ia administration at a dose of 10 mg/kg
|
None
|
60.0
%
|
|
Journal : J. Med. Chem.
Title : New alpha-thiol dipeptide dual inhibitors of angiotensin-I converting enzyme and neutral endopeptidase EC 3.4.24.11.
Year : 1995
Volume : 38
Issue : 26
First Page : 5023
Last Page : 5030
Authors : Fink CA, Qiao Y, Berry CJ, Sakane Y, Ghai RD, Trapani AJ.
Abstract : Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I converting enzyme, have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. A novel series of alpha-thio dipeptides containing central cyclic non-natural amino acids were prepared and were evaluated for their ability to inhibit these two metallopeptidases in vitro and in vivo. Most of these compounds were found to be excellent dual inhibitors of ACE and NEP in vitro and several were also found to inhibit angiotensin-I (AI) pressor response in conscious rats when given by intravenous administration. Compound 6n, one of our most potent dual inhibitors in vitro, was found to be more efficacious than captopril in the AI pressor experiment when administered orally to conscious rats. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. The structure-activity relationships and biological activity of these dual inhibitors will be discussed.
|
Evaluation of plasma inhibition of Angiotensin I converting enzyme activity in conscious rat 4 hours after ia administration at a dose of 10 mg/kg
|
None
|
26.0
%
|
|
Journal : J. Med. Chem.
Title : New alpha-thiol dipeptide dual inhibitors of angiotensin-I converting enzyme and neutral endopeptidase EC 3.4.24.11.
Year : 1995
Volume : 38
Issue : 26
First Page : 5023
Last Page : 5030
Authors : Fink CA, Qiao Y, Berry CJ, Sakane Y, Ghai RD, Trapani AJ.
Abstract : Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I converting enzyme, have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. A novel series of alpha-thio dipeptides containing central cyclic non-natural amino acids were prepared and were evaluated for their ability to inhibit these two metallopeptidases in vitro and in vivo. Most of these compounds were found to be excellent dual inhibitors of ACE and NEP in vitro and several were also found to inhibit angiotensin-I (AI) pressor response in conscious rats when given by intravenous administration. Compound 6n, one of our most potent dual inhibitors in vitro, was found to be more efficacious than captopril in the AI pressor experiment when administered orally to conscious rats. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. The structure-activity relationships and biological activity of these dual inhibitors will be discussed.
|
Evaluation of plasma inhibition of Angiotensin I converting enzyme activity in conscious rat 4 hr after oral administration at a dose of 10 mg/kg
|
None
|
36.0
%
|
|
Journal : J. Med. Chem.
Title : New alpha-thiol dipeptide dual inhibitors of angiotensin-I converting enzyme and neutral endopeptidase EC 3.4.24.11.
Year : 1995
Volume : 38
Issue : 26
First Page : 5023
Last Page : 5030
Authors : Fink CA, Qiao Y, Berry CJ, Sakane Y, Ghai RD, Trapani AJ.
Abstract : Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I converting enzyme, have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. A novel series of alpha-thio dipeptides containing central cyclic non-natural amino acids were prepared and were evaluated for their ability to inhibit these two metallopeptidases in vitro and in vivo. Most of these compounds were found to be excellent dual inhibitors of ACE and NEP in vitro and several were also found to inhibit angiotensin-I (AI) pressor response in conscious rats when given by intravenous administration. Compound 6n, one of our most potent dual inhibitors in vitro, was found to be more efficacious than captopril in the AI pressor experiment when administered orally to conscious rats. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. The structure-activity relationships and biological activity of these dual inhibitors will be discussed.
|
Evaluation of plasma inhibition of Angiotensin I converting enzyme activity in conscious rat 6 hour after oral administration at a dose of 10 mg/kg
|
None
|
13.0
%
|
|
Journal : J. Med. Chem.
Title : New alpha-thiol dipeptide dual inhibitors of angiotensin-I converting enzyme and neutral endopeptidase EC 3.4.24.11.
Year : 1995
Volume : 38
Issue : 26
First Page : 5023
Last Page : 5030
Authors : Fink CA, Qiao Y, Berry CJ, Sakane Y, Ghai RD, Trapani AJ.
Abstract : Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I converting enzyme, have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. A novel series of alpha-thio dipeptides containing central cyclic non-natural amino acids were prepared and were evaluated for their ability to inhibit these two metallopeptidases in vitro and in vivo. Most of these compounds were found to be excellent dual inhibitors of ACE and NEP in vitro and several were also found to inhibit angiotensin-I (AI) pressor response in conscious rats when given by intravenous administration. Compound 6n, one of our most potent dual inhibitors in vitro, was found to be more efficacious than captopril in the AI pressor experiment when administered orally to conscious rats. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. The structure-activity relationships and biological activity of these dual inhibitors will be discussed.
|
Evaluation of plasma inhibition of Angiotensin I converting enzyme activity in conscious rat 6 hours after ia administration at a dose of 10 mg/kg
|
None
|
3.0
%
|
|
Journal : J. Med. Chem.
Title : New alpha-thiol dipeptide dual inhibitors of angiotensin-I converting enzyme and neutral endopeptidase EC 3.4.24.11.
Year : 1995
Volume : 38
Issue : 26
First Page : 5023
Last Page : 5030
Authors : Fink CA, Qiao Y, Berry CJ, Sakane Y, Ghai RD, Trapani AJ.
Abstract : Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I converting enzyme, have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. A novel series of alpha-thio dipeptides containing central cyclic non-natural amino acids were prepared and were evaluated for their ability to inhibit these two metallopeptidases in vitro and in vivo. Most of these compounds were found to be excellent dual inhibitors of ACE and NEP in vitro and several were also found to inhibit angiotensin-I (AI) pressor response in conscious rats when given by intravenous administration. Compound 6n, one of our most potent dual inhibitors in vitro, was found to be more efficacious than captopril in the AI pressor experiment when administered orally to conscious rats. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. The structure-activity relationships and biological activity of these dual inhibitors will be discussed.
|
Inhibition of Angiotensin I converting enzyme (ACE)
|
None
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Toward an optimal joint recognition of the S1' subsites of endothelin converting enzyme-1 (ECE-1), angiotensin converting enzyme (ACE), and neutral endopeptidase (NEP).
Year : 2002
Volume : 45
Issue : 7
First Page : 1477
Last Page : 1486
Authors : Inguimbert N, Coric P, Poras H, Meudal H, Teffot F, Fournié-Zaluski MC, Roques BP.
Abstract : The formation of vasoconstrictors (e.g., angiotensin II and endothelin) and the inactivation of vasodilators (e.g., bradykinin and atrial natriuretic) by membrane-bound zinc metallopeptidases are key mechanisms in the control of blood pressure and fluid homeostasis. The way in which these peptides modulate physiological functions has been intensively studied. With the aim to develop compounds that can jointly block the three metallopeptidases-neutral endopeptidase (NEP, neprilysin), angiotensin-converting enzyme (ACE), and endothelin-converting enzyme (ECE-1)-we studied the common structural specificity of the S1' subsites of these peptidases. Various mercaptoacyl amino acids of the general formula HS-CH2-CH(R1')CO-Trp-OH, possessing more or less constrained R1' side chains, were designed. The mercapto-acyl synthons contain one or two asymmetrical centers. The K(i) values of the separated stereoisomers of the most efficient inhibitors were used to determine the stereochemical preference of each enzyme. A guideline for the joint inhibition of the three peptidases was obtained with the (2R,3R) isomer of compound 13b. Its K(i) values on NEP, ACE, and ECE were 0.7, 43, and 26 nM, respectively.
|
Compound was tested for plasma inhibition of Angiotensin I converting enzyme activity in the conscious rat. Expressed as Inhibition of AI pressor response at 1 hr at a dose of 10 mg/kg po
|
None
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Mercaptoacyl dipeptides as orally active dual inhibitors of angiotensin-converting enzyme and neutral endopeptidase.
Year : 1996
Volume : 39
Issue : 16
First Page : 3158
Last Page : 3168
Authors : Fink CA, Carlson JE, McTaggart PA, Qiao Y, Webb R, Chatelain R, Jeng AY, Trapani AJ.
Abstract : Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I-converting enzyme (ACE, EC 2.4.15.1), have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. We have previously reported that compound 2 (N-[[1-[(2(S)-mercapto-3-methyl-1-oxobutyl) amino]-1-cyclopentyl]-carbonyl]-L-tyrosine) was a potent dual inhibitor in vitro (IC50 (ACE) = 7.0 nM, IC50 (NEP) = 1.5 nM) (Fink et al. J. Med. Chem. 1995, 38, 5023-5030). This compound was found to have oral activity; however, its duration of effect was short. A series of thioacetate carboxylic acid ester analogs of compound 2 was prepared. Modifications were also made to the tyrosine phenol. These compounds were evaluated for their ability to inhibit plasma ACE activity when administered orally to conscious normotensive rats. Most of the compounds prepared were found to be orally active with longer durations of effect than compound 2. Compound 38 (N-[[1-[(2(S)-(acetylthio)-3-methyl-1-oxobutyl) amino]-1-cyclopentyl]carbonyl]-O-methyl-L-tyrosine ethyl ester), administered at 11.7 mg/kg po, was found to be more efficacious than captopril at 10 mg/kg po. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. Compound 38 was found to lower blood pressure in the aorta-ligated rat and the spontaneously hypertensive rat when administered orally. The synthesis and biological activity of these dual inhibitors are discussed.
|
Compound was tested for plasma inhibition of Angiotensin I converting enzyme activity in the conscious rat. Expressed as Inhibition of AI pressor response at 2 hr at a dose of 10 mg/kg po
|
None
|
78.0
%
|
|
Journal : J. Med. Chem.
Title : Mercaptoacyl dipeptides as orally active dual inhibitors of angiotensin-converting enzyme and neutral endopeptidase.
Year : 1996
Volume : 39
Issue : 16
First Page : 3158
Last Page : 3168
Authors : Fink CA, Carlson JE, McTaggart PA, Qiao Y, Webb R, Chatelain R, Jeng AY, Trapani AJ.
Abstract : Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I-converting enzyme (ACE, EC 2.4.15.1), have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. We have previously reported that compound 2 (N-[[1-[(2(S)-mercapto-3-methyl-1-oxobutyl) amino]-1-cyclopentyl]-carbonyl]-L-tyrosine) was a potent dual inhibitor in vitro (IC50 (ACE) = 7.0 nM, IC50 (NEP) = 1.5 nM) (Fink et al. J. Med. Chem. 1995, 38, 5023-5030). This compound was found to have oral activity; however, its duration of effect was short. A series of thioacetate carboxylic acid ester analogs of compound 2 was prepared. Modifications were also made to the tyrosine phenol. These compounds were evaluated for their ability to inhibit plasma ACE activity when administered orally to conscious normotensive rats. Most of the compounds prepared were found to be orally active with longer durations of effect than compound 2. Compound 38 (N-[[1-[(2(S)-(acetylthio)-3-methyl-1-oxobutyl) amino]-1-cyclopentyl]carbonyl]-O-methyl-L-tyrosine ethyl ester), administered at 11.7 mg/kg po, was found to be more efficacious than captopril at 10 mg/kg po. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. Compound 38 was found to lower blood pressure in the aorta-ligated rat and the spontaneously hypertensive rat when administered orally. The synthesis and biological activity of these dual inhibitors are discussed.
|
In vitro inhibitory activity was evaluated against angiotensin converting enzyme from rabbit in bovine buffered base
|
Oryctolagus cuniculus
|
3.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A new potent inhibitor for angiotensin converting enzyme: (R,S)-captopril-F3
Year : 1991
Volume : 1
Issue : 11
First Page : 581
Last Page : 584
Authors : Ojima I, Jameison FA
|
In vitro inhibitory activity was evaluated against angiotensin converting enzyme from rabbit in bovine buffered base. (reported from ref. 1b)
|
Oryctolagus cuniculus
|
2.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A new potent inhibitor for angiotensin converting enzyme: (R,S)-captopril-F3
Year : 1991
Volume : 1
Issue : 11
First Page : 581
Last Page : 584
Authors : Ojima I, Jameison FA
|
Inhibitory concentration against angiotensin converting enzyme (ACE)
|
Oryctolagus cuniculus
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel angiotensin converting enzyme inhibitors containing -hydroxy ketomethylene dipeptide isosteres
Year : 1994
Volume : 4
Issue : 23
First Page : 2799
Last Page : 2804
Authors : Kim BH, Ryu EJ, Chung YJ
|
In vitro inhibition against angiotensin converting enzyme (ACE)
|
None
|
23.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-Substituted proline derivatives that inhibit angiotensin converting enzyme and neutral endopeptidase 24.11.
Year : 1994
Volume : 4
Issue : 22
First Page : 2673
Last Page : 2676
Authors : Bhagwat SS, Fink CA, Gude C, Chan K, Qiao Y, Sakane Y, Berry C, Ghai RD
|
In vitro inhibitory concentration against angiotensin-converting enzyme
|
None
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Dual inhibition of neutral endopeptidase and angiotensin-converting enzyme by N-phosphonomethyl and N-carboxyalkyl dipeptides
Year : 1994
Volume : 4
Issue : 22
First Page : 2715
Last Page : 2720
Authors : De Lombaert S, Tan J, Stamford LJ, Sakane Y, Berry C, Ghai RD
|
Compound was tested for plasma inhibition of Angiotensin I converting enzyme activity in the conscious rat. Expressed as Inhibition of AI pressor response at 4 hr at a dose of 10 mg/kg po
|
None
|
36.0
%
|
|
Journal : J. Med. Chem.
Title : Mercaptoacyl dipeptides as orally active dual inhibitors of angiotensin-converting enzyme and neutral endopeptidase.
Year : 1996
Volume : 39
Issue : 16
First Page : 3158
Last Page : 3168
Authors : Fink CA, Carlson JE, McTaggart PA, Qiao Y, Webb R, Chatelain R, Jeng AY, Trapani AJ.
Abstract : Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I-converting enzyme (ACE, EC 2.4.15.1), have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. We have previously reported that compound 2 (N-[[1-[(2(S)-mercapto-3-methyl-1-oxobutyl) amino]-1-cyclopentyl]-carbonyl]-L-tyrosine) was a potent dual inhibitor in vitro (IC50 (ACE) = 7.0 nM, IC50 (NEP) = 1.5 nM) (Fink et al. J. Med. Chem. 1995, 38, 5023-5030). This compound was found to have oral activity; however, its duration of effect was short. A series of thioacetate carboxylic acid ester analogs of compound 2 was prepared. Modifications were also made to the tyrosine phenol. These compounds were evaluated for their ability to inhibit plasma ACE activity when administered orally to conscious normotensive rats. Most of the compounds prepared were found to be orally active with longer durations of effect than compound 2. Compound 38 (N-[[1-[(2(S)-(acetylthio)-3-methyl-1-oxobutyl) amino]-1-cyclopentyl]carbonyl]-O-methyl-L-tyrosine ethyl ester), administered at 11.7 mg/kg po, was found to be more efficacious than captopril at 10 mg/kg po. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. Compound 38 was found to lower blood pressure in the aorta-ligated rat and the spontaneously hypertensive rat when administered orally. The synthesis and biological activity of these dual inhibitors are discussed.
|
Compound was tested for plasma inhibition of Angiotensin I converting enzyme activity in the conscious rat. Expressed as Inhibition of AI pressor response at 6 hr at a dose of 10 mg/kg po
|
None
|
13.0
%
|
|
Journal : J. Med. Chem.
Title : Mercaptoacyl dipeptides as orally active dual inhibitors of angiotensin-converting enzyme and neutral endopeptidase.
Year : 1996
Volume : 39
Issue : 16
First Page : 3158
Last Page : 3168
Authors : Fink CA, Carlson JE, McTaggart PA, Qiao Y, Webb R, Chatelain R, Jeng AY, Trapani AJ.
Abstract : Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I-converting enzyme (ACE, EC 2.4.15.1), have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. We have previously reported that compound 2 (N-[[1-[(2(S)-mercapto-3-methyl-1-oxobutyl) amino]-1-cyclopentyl]-carbonyl]-L-tyrosine) was a potent dual inhibitor in vitro (IC50 (ACE) = 7.0 nM, IC50 (NEP) = 1.5 nM) (Fink et al. J. Med. Chem. 1995, 38, 5023-5030). This compound was found to have oral activity; however, its duration of effect was short. A series of thioacetate carboxylic acid ester analogs of compound 2 was prepared. Modifications were also made to the tyrosine phenol. These compounds were evaluated for their ability to inhibit plasma ACE activity when administered orally to conscious normotensive rats. Most of the compounds prepared were found to be orally active with longer durations of effect than compound 2. Compound 38 (N-[[1-[(2(S)-(acetylthio)-3-methyl-1-oxobutyl) amino]-1-cyclopentyl]carbonyl]-O-methyl-L-tyrosine ethyl ester), administered at 11.7 mg/kg po, was found to be more efficacious than captopril at 10 mg/kg po. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. Compound 38 was found to lower blood pressure in the aorta-ligated rat and the spontaneously hypertensive rat when administered orally. The synthesis and biological activity of these dual inhibitors are discussed.
|
Inhibition of angiotensin I converting enzyme in silico
|
None
|
79.43
nM
|
|
Journal : J. Med. Chem.
Title : Validation of EGSITE2, a mixed integer program for deducing objective site models for experimental binding data.
Year : 1997
Volume : 40
Issue : 20
First Page : 3161
Last Page : 3172
Authors : Crippen GM.
Abstract : EGSITE2 represents a substantial advance in a long series of methods for calculating receptor site models given only specific binding data. Compared to our most recently reported technique, EGSITE [Schnitker et al. J. Comput.-Aided Mol. Des. 1997, 11, 93-110] the user no longer has to simplify the structures of the molecules in the training set by clustering the atoms into a few superatoms. The only remaining source of subjectivity is the user's choice of compounds for the training set, which can be surprisingly few in number. Then EGSITE2 automatically produces typically several different models that explain the observed binding without outliers. The models are remarkably simple but have substantial predictive power for any sort of test compound, with an estimation of the uncertainty of the prediction. Validation of the method is reported for four standard test cases: triazines and pyrimidines binding to dihydrofolate reductase, steroids binding to corticosteroid-binding globulin and to testosterone-binding globulin, and peptides binding to angiotensin-converting enzyme.
|
Inhibition of Angiotensin I converting enzyme
|
None
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational analysis and active site modelling of angiotensin-converting enzyme inhibitors.
Year : 1985
Volume : 28
Issue : 3
First Page : 393
Last Page : 399
Authors : Andrews PR, Carson JM, Caselli A, Spark MJ, Woods R.
Abstract : The discovery of captopril as a potent, orally active inhibitor of angiotensin-converting enzyme (ACE) led to the recent development of many series of novel structures with similar biological activity. To date, however, all of these inhibitors are flexible or semiflexible molecules, and there is therefore no clear definition of the conformational requirements for ACE inhibition. In an effort to solve this problem, we have carried out conformational energy calculations on a series of eight structurally diverse ACE inhibitors. Comparison of the low-energy conformations available to these molecules leads to the conclusion that there is a common low-energy conformation throughout the series. The calculations thus define the structural and conformational requirements for ACE inhibition. Expansion of this model to the receptor level has been achieved by considering possible alternative receptor sites for each of the molecules in its proposed biologically active conformation and leads to an active-site model for ACE which may be useful for the design of further inhibitors.
|
In vitro inhibitory activity against Angiotensin I converting enzyme
|
None
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Angiotensin-converting enzyme inhibitors: synthesis and biological activity of acyl tripeptide analogues of enalapril.
Year : 1985
Volume : 28
Issue : 4
First Page : 434
Last Page : 442
Authors : Greenlee WJ, Allibone PL, Perlow DS, Patchett AA, Ulm EH, Vassil TC.
Abstract : The synthesis and biological activity of a series of inhibitors of angiotensin-converting enzyme (EC 3.4.15.1) are described. Incorporation of the substituted N-carboxymethyl dipeptide design of enalapril (MK-421) into acyl tripeptides and larger peptides yielded potent inhibitors of the enzyme. These can be viewed as substrate analogues in which the carbonyl of the scissile peptide bond is replaced by a CHCO2H group. Several of the analogues described possess inhibitory potency equal to that of enalaprilat (MK-422), but none achieves an increase in potency which would demonstrate additional binding interactions contributed by the extended peptide chain. Application of the design described may be useful for inhibition of other metallopeptidases.
|
Compound tested in vitro for inhibition of Angiotensin I converting enzyme
|
None
|
12.9
nM
|
|
Journal : J. Med. Chem.
Title : Angiotensin converting enzyme inhibitors: spirapril and related compounds.
Year : 1989
Volume : 32
Issue : 7
First Page : 1600
Last Page : 1606
Authors : Smith EM, Swiss GF, Neustadt BR, McNamara P, Gold EH, Sybertz EJ, Baum T.
Abstract : The synthesis of spirapril (5), spiraprilat (25), their RSS stereoisomers, and their glycyl (18b) and lysyl (36, 37) analogues is described. These compounds were evaluated in vivo for inhibition of angiotensin converting enzyme (ACE), and selected compounds were evaluated for in vitro ACE inhibition (spirapril ID50 16 micrograms/kg; spiraprilat IC50 0.8 nM, ID50 8 micrograms/kg). In anesthetized rats, iv, esters 5 and 36 are more potent than enalapril, and diacids 25 and 37 are more potent than enalaprilat in vitro. In the conscious rats, orally, 5 and enalapril (2) showed potent and sustained activity at doses of 0.03-1 and 0.1-1 mg/kg, respectively. From this work, spirapril was selected for clinical evaluation as an antihypertensive agent.
|
Compound was tested for inhibitory activity against Angiotensin I converting enzyme
|
None
|
30.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Thiol and hydroxamic acid containing inhibitors of endothelin converting enzyme
Year : 1993
Volume : 3
Issue : 10
First Page : 1953
Last Page : 1958
Authors : Bertenshaw SR, Talley JJ, Rogers RS, Carter JS, Moore WM, Branson LM, Koboldt CM
|
In vitro inhibitory activity against Angiotensin I converting enzyme
|
None
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : Angiotensin converting enzyme inhibitors: structure-activity profile of 1-benzazepin-2-one derivatives.
Year : 1985
Volume : 28
Issue : 11
First Page : 1603
Last Page : 1606
Authors : Stanton JL, Watthey JW, Desai MN, Finn BM, Babiarz JE, Tomaselli HC.
Abstract : The preparation of a series of 3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid derivatives 5a-y by reductive amination of 2,3,4,5-tetrahydro-1H-1-benzazepine-2,3-dione (7) with L-amino acid derivatives is described. The compounds were tested for inhibition of angiotensin converting enzyme. The structure-activity profile of the series is discussed. Compound 5a was especially potent when tested in dogs for inhibition of angiotensin I pressor response, having an ID50 = 0.07 mg/kg po.
|
Inhibitory activity against angiotensin converting enzyme (ACE)
|
None
|
22.91
nM
|
|
Journal : J. Med. Chem.
Title : Three-dimensional quantitative structure-activity relationship of angiotesin-converting enzyme and thermolysin inhibitors. II. A comparison of CoMFA models incorporating molecular orbital fields and desolvation free energies based on active-analog and complementary-receptor-field alignment rules.
Year : 1993
Volume : 36
Issue : 16
First Page : 2390
Last Page : 2403
Authors : Waller CL, Marshall GR.
Abstract : The utility of comparative molecular field analysis (CoMFA), a three-dimensional Quantitative Structure-Activity Relationship (3-D QSAR) paradigm, as a tool to aid in the development of predictive models has been previously addressed (Depriest, S.D. et al., J. Am. Chem. Soc. 1993, in press). Although predictive correlations were obtained for angiotensin-converting and thermolysin inhibitors, certain inadequacies of the CoMFA technique were noted. Primarily, CoMFA steric and electrostatic fields alone do not fully characterize the zinc-ligand interaction. Previously, this was partially rectified by the inclusion of indicator variables into the QSAR table to designate the class of zinc-binding ligand. Recent advances in molecular modeling technology have allowed us to further address this limitation of the preceding study. Using molecular orbital fields derived from semiempirical calculations as additional descriptors in the QSAR table, predictive correlations were produced based on CoMFA and molecular orbital fields alone--indicator variables no longer being necessary. Arbitrary information concerning the alignment of molecules under study within the active-site introduces ambiguities into the CoMFA study. Crystallographic information detailing the binding mode of several thermolysin enzyme inhibitors has previously been used as a guide for the alignment of additional, noncrystallized, inhibitors. However, this process was complicated by the lack of parameters for zinc in the molecular mechanical force field. Therefore, zinc-ligand interactions were ignored during the standard minimization procedure. The use of field-fit minimization using complementary receptor fields as templates is presented as a possible solution to the problem. Predictive correlations were obtained from analyses based on this method of molecular alignment. The availability of crystallographic data for thermolysin enzyme-inhibitor complexes allowed for an alternate definition of the CoMFA region. Herein, promising results from analyses using actual receptor active-site atom probe atoms are presented.
|
Percentage inactivation of the angiotensin I induced vasopressor response in normotensive conscious rats after po administration at dose 0.15 mg/kg; 65-68
|
None
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Angiotensin-converting enzyme inhibitors: new orally active 1,4-thiazepine-2,5-diones, 1,4-thiazine-2,5-diones, and 1,4-benzothiazepine-2,5-diones possessing antihypertensive activity.
Year : 1986
Volume : 29
Issue : 5
First Page : 784
Last Page : 796
Authors : Skiles JW, Suh JT, Williams BE, Menard PR, Barton JN, Loev B, Jones H, Neiss ES, Schwab A, Mann WS.
Abstract : The preparation of a series of 1,4-thiazepine-2,5-diones, 1,4-thiazine-2,5-diones, and 1,4-benzothiazepine-2,5-diones and their ability in inhibiting the activity of angiotensin-converting enzyme (ACE) in vitro and in vivo were examined. These compounds are assumed to act as prodrugs since they undergo rapid ring-opening reactions to give the corresponding biologically active free SH compounds when incubated with rat plasma or when treated with aqueous 0.1 N HCl or phosphate buffer (pH 7.4). The thiazepines 23-25 and 30 are potent inhibitors of ACE when administered po to rats and are comparable in potency to captopril (1). The most active thiazines in rats, po, were 42 and 45. Of the benzothiazepines studied, 22a was the most active in inhibiting ACE in the conscious normotensive rat, ID50 = 0.15 mg/kg, po. The acute antihypertensive effects of oral administration of a number of these compounds on mean arterial pressure and heart rate were studied in spontaneously hypertensive rats (SHR) maintained on a sodium-deficient diet.
|
In vitro inhibitory activity against rat serum angiotensin I converting enzyme using hippuryl-glycyl-glycine as substrate
|
None
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : 1,2-Cyclomethylenecarboxylic monoamide hydroxamic derivatives. A novel class of non-amino acid angiotensin converting enzyme inhibitors.
Year : 1993
Volume : 36
Issue : 6
First Page : 699
Last Page : 707
Authors : Turbanti L, Cerbai G, Di Bugno C, Giorgi R, Garzelli G, Criscuoli M, Renzetti AR, Subissi A, Bramanti G, DePriest SA.
Abstract : A series of monoamidic derivatives of cis- and trans-1,2-cyclohexanedicarboxylic and 1,2-cyclopentanedicarboxylic acids bearing either a carboxylic, sulfhydrylic, or hydroxamic group in the side chain were synthesized and evaluated in vitro for their inhibitory activity against angiotensin converting enzyme. The compounds were designed as potential ACE inhibitors of novel structure, assuming that a monoamidic residue of an 1,2-cyclomethylenedicarboxylic acid could be an alternative structure to the acylproline moiety, the carboxyl-terminal portion common to various ACE inhibitors. The most active compounds were found in the hydroxamic derivatives of cyclohexane series; within this series of derivatives a marked increase of potency was caused by alkylation of the amidic nitrogen with a methyl or ethyl group. Therefore enantiomers of the selected hydroxamic derivatives of cis- and trans-1,2-cyclohexanedicarboxylic acid were prepared by two different chiral synthetic routes and evaluated in vitro for their ACE inhibitor potencies. The active enantiomers both of the cis series (21a, 21c) and trans series (16b, 16d) were found to have all R configuration at the C-2 and R or S configuration at the C-1, while in the classical ACE inhibitors S configuration at the terminal carboxylate (corresponding to the C-1 of our compounds) is strictly required for activity. The most potent compound of the series was (1S,2R)-cis-2[[[2-(hydroxyamino)-2-oxoethyl]methylamino]carbonyl] cyclohexanecarboxylic acid (21a) with an IC50 value of 7.0 nM compared with the value of 3.0 nM for captopril. Further 21a was shown to be highly selective and competitive ACE inhibitor. These results indicate that this non-amino acid structure of inhibitors meets the ACE active site requirements for the binding. The binding compatibility of the most active compounds with a model of ACE active site was evaluated by molecular modeling techniques.
|
Inhibition of guinea pig serum Angiotensin I converting enzyme
|
Cavia porcellus
|
9.0
nM
|
|
Journal : J. Med. Chem.
Title : Derivatives of the potent angiotensin converting enzyme inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline: effect of changes at positions 2 and 5 of the hexanoic acid portion.
Year : 1982
Volume : 25
Issue : 11
First Page : 1292
Last Page : 1299
Authors : Almquist RG, Crase J, Jennings-White C, Meyer RF, Hoefle ML, Smith RD, Essenburg AD, Kaplan HR.
Abstract : Several derivatives of the potent angiotensin converting enzyme inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline (1) were synthesized and tested for converting enzyme inhibition activity and blood pressure lowering effects in rats. One compound, 5(S)-benzamido-2(R)-methyl-4-oxo-6-phenylhexanoyl-L-proline (2a), had and I50 against angiotensin converting enzyme of 1.0 x 10(-9) M and is the most potent inhibitor prepared thus far in this class of compounds. Testing of 2a orally at 30 mg/kg for inhibition of the angiotensin I induced blood pressure increase in conscious normotensive rats gave 100% inhibition that required 143 min before the angiotensin I blood pressure response returned to 70% of the pretreatment control response. In the conscious renal hypertensive rat, 2a given orally at a dose of 3 mg/kg caused a lowering of blood pressure that reached its maximum of 40 mmHg 8 h following drug administration.
|
Concentration required to inhibit the activity of Angiotensin I converting enzyme by 50%
|
Cavia porcellus
|
9.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel synthesis of (S)-1-[5-(benzoylamino)-1,4-dioxo-6-phenylhexyl]-L-proline and analogues: potent angiotensin converting enzyme inhibitors.
Year : 1981
Volume : 24
Issue : 8
First Page : 964
Last Page : 969
Authors : Meyer RF, Nicolaides ED, Tinney FJ, Lunney EA, Holmes A, Hoefle ML, Smith RD, Essenburg AD, Kaplan HR, Almquist RG.
Abstract : A new approach was developed for the synthesis of (S)-1-[5-(benzoylamino)-1,4-dioxo-6-phenylhexyl]-L-proline (1) and 23 analogues. The delta-(acylamino)-gamma-keto acid intermediates were obtained by a modified Dakin--West reaction using 3-carbomethoxypropionyl chloride. Acylation of L-proline and recrystallization of the mixture of diastereomers gave the optically pure title compound in three reaction steps. The in vitro angiotensin converting enzyme (ACE) inhibitory activity of 1 was confirmed. Some of the novel analogues (6, 11, 13, and 17) were also found to be potent inhibitors of ACE in vitro with an IC50 of 1.4-8.8 x 10(-9) M (IC50 for captopril = 0.9 x 10(-8) M). In vivo these compounds (6, 11, 17, and 18) were much less active than captopril, especially by the oral route. Against angiotensin I (AI) challenge in normotensive conscious rats, 1 and 6 produced less than 50% inhibition at 30 mg/kg po but 57 to 82% inhibition at 3 mg/kg iv. Inhibition by both routes lasted less than 1 h. In renal hypertensive rats, 1 and 15 of its analogues failed to produce significant blood pressure lowering effects, in contrast to the marked effects of captopril. Near maximum inhibition of AI was achieved by continuous intravenous infusions of 1 and 20, suggesting that limited oral activity may by due to degradation and/or clearance.
|
Concentration required for 50% inhibition of Angiotensin I converting enzyme
|
Cavia porcellus
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and angiotensin-converting enzyme inhibitory activity of 3-(Mercaptomethyl)-2-oxo-1-pyrrolidineacetic acids and 3-(Mercaptomethyl)-2-oxo-1-piperidineacetic acids.
Year : 1981
Volume : 24
Issue : 1
First Page : 104
Last Page : 109
Authors : Klutchko S, Hoefle ML, Smith RD, Essenburg AD, Parker RB, Nemeth VL, Ryan MJ, Dugan DH, Kaplan HR.
Abstract : A number of gamma- and delta-lactam derivatives were synthesized and their in vitro angiotensin-converting enzyme (ACE) inhibitory activities were compared. The structures of these compounds were designed to include many of the important features of captopril. The synthesis involved the preparation of a variety of novel 3-methylene-2-pyrrolidinones (3-5 and 16) and 3-methylene-2-piperidinones (3a-5a, 10-12, and 17). The key intermediate 3-methylenelactams 3 and 3a were obtained from 3-(hydroxymethyl)lactams 2 and 2a by a direct dehydration with dicyclohexylcarbodiimide using cuprous iodide as a catalyst. Introduction of the sulfhydryl group was accomplished by a Michael addition of these alpha, beta-unsaturated lactams. The compound with the highest in vitro activity was 3-(mercaptomethyl)-2-oxo-1-piperidineacetic acid (7a). The activity of the 7a both in vitro and in vivo (dog) was shown to be less than that of captopril by a factor of about 100.
|
Inhibition of guinea pig angiotensin I converting enzyme
|
Cavia porcellus
|
13.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel angiotensin converting enzyme inhibitor quinapril and related compounds. A divergence of structure-activity relationships for non-sulfhydryl and sulfhydryl types.
Year : 1986
Volume : 29
Issue : 10
First Page : 1953
Last Page : 1961
Authors : Klutchko S, Blankley CJ, Fleming RW, Hinkley JM, Werner AE, Nordin I, Holmes A, Hoefle ML, Cohen DM, Essenburg AD.
Abstract : The synthesis and angiotensin converting enzyme (ACE) inhibiting activities of quinapril (CI-906, 22), its active diacid (CI-928, 33), and its dimethoxy analogue (CI-925, 25) are reported. These tetrahydro-3-isoquinolinecarboxylic acid derivatives possess equivalent in vitro potency and in vivo efficacy to enalapril. Sulfhydryl analogues with the same structural variation are also highly potent. In contrast, tetrahydro-1-isoquinolinecarboxylic acid and homologous isoindoline-1-carboxylic acid analogues show a striking divergence in potency between the two types, sulfhydryl analogues being essentially inactive, while non-sulfhydryl analogues are equipotent with the proline prototype. This is the first evidence suggesting that alternate binding modes may exist for the two major structural classes of small molecule ACE inhibitors.
|
In vitro inhibition of Angiotensin I converting enzyme in Hog plasma
|
Sus scrofa
|
25.0
nM
|
|
Journal : J. Med. Chem.
Title : Angiotensin converting enzyme inhibitors. 10. Aryl sulfonamide substituted N-[1-carboxy-3-phenylpropyl]-L-alanyl-L-proline derivatives as novel antihypertensives.
Year : 1990
Volume : 33
Issue : 6
First Page : 1606
Last Page : 1615
Authors : Mencel JJ, Regan JR, Barton J, Menard PR, Bruno JG, Calvo RR, Kornberg BE, Schwab A, Neiss ES, Suh JT.
Abstract : Compounds 1a-g consisting of enalaprilat covalently bonded to aryl sulfonamides, including several known thiazide diuretics, were synthesized and tested for ACE inhibitory and diuretic and overall antihypertensive effects. All compounds were potent ACE inhibitors in vitro, with IC50 = 6.5-85 nM. At 10 mg/kg iv or ip in the rat, 1a-g inhibited the AI pressor response by 76-100%; inhibition declined significantly upon oral dosing. Compounds 1a and 1f at 100 mg/kg ip in the sodium-depleted, spontaneously hypertensive rats reduced blood pressure 28-35% and 41-42%, respectively. Compounds 1a and 1f elicited natriuresis and kaliuresis without accompanying volume increases in the rat; 1c at 25 mg/kg iv induced delayed diuresis. Compound 1f has been chosen for further development.
|
In vivo inhibition of Angiotensin I converting enzyme in hog plasma after (po) administration of a dose of 0.3(mg/kg)
|
Sus scrofa
|
64.0
%
|
|
Journal : J. Med. Chem.
Title : Angiotensin converting enzyme inhibitors. 10. Aryl sulfonamide substituted N-[1-carboxy-3-phenylpropyl]-L-alanyl-L-proline derivatives as novel antihypertensives.
Year : 1990
Volume : 33
Issue : 6
First Page : 1606
Last Page : 1615
Authors : Mencel JJ, Regan JR, Barton J, Menard PR, Bruno JG, Calvo RR, Kornberg BE, Schwab A, Neiss ES, Suh JT.
Abstract : Compounds 1a-g consisting of enalaprilat covalently bonded to aryl sulfonamides, including several known thiazide diuretics, were synthesized and tested for ACE inhibitory and diuretic and overall antihypertensive effects. All compounds were potent ACE inhibitors in vitro, with IC50 = 6.5-85 nM. At 10 mg/kg iv or ip in the rat, 1a-g inhibited the AI pressor response by 76-100%; inhibition declined significantly upon oral dosing. Compounds 1a and 1f at 100 mg/kg ip in the sodium-depleted, spontaneously hypertensive rats reduced blood pressure 28-35% and 41-42%, respectively. Compounds 1a and 1f elicited natriuresis and kaliuresis without accompanying volume increases in the rat; 1c at 25 mg/kg iv induced delayed diuresis. Compound 1f has been chosen for further development.
|
Inhibitory activity against angiotensin I converting enzyme (ACE)
|
None
|
23.0
nM
|
|
Journal : J. Med. Chem.
Title : Protease inhibitors: current status and future prospects.
Year : 2000
Volume : 43
Issue : 3
First Page : 305
Last Page : 341
Authors : Leung D, Abbenante G, Fairlie DP.
|
Compound is evaluated for the inhibition of guinea pig ileum contraction caused by 25 ng/mL angiotensin I
|
Cavia porcellus
|
0.05
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of a ketomethylene analogue of a tripeptide inhibitor of angiotensin converting enzyme.
Year : 1980
Volume : 23
Issue : 12
First Page : 1392
Last Page : 1398
Authors : Almquist RG, Chao WR, Ellis ME, Johnson HL.
Abstract : An analogue of a tripeptide inhibitor of angiotensin converting enzyme, Bz-Phe-Gly-Pro, has been synthesized in which the amide bond connecting phenylalanine and glycine has been replaced by a ketomethylene group. This nonpeptide analogue, 20, shows more potent converting enzyme inhibiting activity, I50 = 0.07 microM, than Bz-Phe-Gly-Pro, I50 = 9.4 microM, or than the orally active D-3-mercapto-2-methylpropanoyl-L-proline (captopril, 1), I50 = 0.30 microM. Compound 20 has a Ki of 1.06 X 10(-7) and either competitive or noncompetitive enzyme kinetics depending on what substrate is used in the converting enzyme assay. In tests for inhibition of angiotensin I induced contractions in the guinea pig ileum, 20 has one-tenth the activity of 1.
|
Inhibitory activity against Leukotriene A4 hydrolase from human leukocytes
|
Homo sapiens
|
70.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Probing the inhibition of leukotriene A4 hydrolase based on its aminopeptidase activity
Year : 1991
Volume : 1
Issue : 10
First Page : 551
Last Page : 556
Authors : Yuan W, Zhong Z, Wong C, Haeggstrom JZ, Wetterholm A, Samuelsson B
|
Percent inhibition of angiotensin I (AI) pressor response after intravenous administration (dose of 0.05 mg/kg)to conscious normotensive rats
|
Rattus norvegicus
|
82.0
%
|
|
Journal : J. Med. Chem.
Title : Angiotensin converting enzyme inhibitors: 1,5-benzothiazepine derivatives.
Year : 1985
Volume : 28
Issue : 10
First Page : 1517
Last Page : 1521
Authors : Slade J, Stanton JL, Ben-David D, Mazzenga GC.
Abstract : The synthesis of chiral 1,5-benzothiazepines 2a-c, 14a-c, 15c, and 16a prepared from cysteine is described. In vitro inhibition of angiotensin converting enzyme (ACE) is reported for each compound. Compound 2c was the most potent in vitro having an IC50 of 2.95 nM. The ester of 2c, i.e. 14c, was found to inhibit the AI pressor response by 75% at a dose of 0.05 mg/kg iv and by 39% at 1.0 mg/kg po. Additionally, 14c lowered blood pressure in the spontaneous hypertensive rat (SHR) by 35 mmHg, at a dose of 10 mg/kg po.
|
Percent inhibition of angiotensin I (AI) pressor response after oral administration (dose of 1.0 mg/kg) to conscious normotensive rats
|
Rattus norvegicus
|
-45.0
%
|
|
Journal : J. Med. Chem.
Title : Angiotensin converting enzyme inhibitors: 1,5-benzothiazepine derivatives.
Year : 1985
Volume : 28
Issue : 10
First Page : 1517
Last Page : 1521
Authors : Slade J, Stanton JL, Ben-David D, Mazzenga GC.
Abstract : The synthesis of chiral 1,5-benzothiazepines 2a-c, 14a-c, 15c, and 16a prepared from cysteine is described. In vitro inhibition of angiotensin converting enzyme (ACE) is reported for each compound. Compound 2c was the most potent in vitro having an IC50 of 2.95 nM. The ester of 2c, i.e. 14c, was found to inhibit the AI pressor response by 75% at a dose of 0.05 mg/kg iv and by 39% at 1.0 mg/kg po. Additionally, 14c lowered blood pressure in the spontaneous hypertensive rat (SHR) by 35 mmHg, at a dose of 10 mg/kg po.
|
Percent inhibition of angiotensin I pressor response 15 min after iv administration in SHR at 0.03 mg/kg
|
Rattus norvegicus
|
20.0
%
|
|
Journal : J. Med. Chem.
Title : Angiotensin converting enzyme inhibitors: N-substituted monocyclic and bicyclic amino acid derivatives.
Year : 1983
Volume : 26
Issue : 9
First Page : 1267
Last Page : 1277
Authors : Stanton JL, Gruenfeld N, Babiarz JE, Ackerman MH, Friedmann RC, Yuan AM, Macchia W.
Abstract : The synthesis of N-(3-mercaptopropionyl)-N-arylglycines (14a-x),- N-arylalanines (15a,b),-N-cycloalkylglycines (16a-k), and -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids (17a-d), -1,2,3,4-tetrahydroquinoline-2-carboxylic acids (18a-f), and -indoline-2-carboxylic acids (19a-k) is described. In vitro inhibition of angiotensin converting enzyme (ACE) is reported for each compound, and the structure--activity relationship for each series is discussed. The in vivo inhibition of ACE and antihypertensive effects of representative compounds from each series are discussed. The most potent compound, 19d, had an in vitro ACE IC50 of 2.6 X 10(-9) M and lowered blood pressure in spontaneous hypertensive rats 85 mm at a dose of 10 mg/kg po.
|
Percent inhibition of angiotensin I pressor response 15 min after iv administration in SHR at 0.3 mg/kg
|
Rattus norvegicus
|
70.0
%
|
|
Journal : J. Med. Chem.
Title : Angiotensin converting enzyme inhibitors: N-substituted monocyclic and bicyclic amino acid derivatives.
Year : 1983
Volume : 26
Issue : 9
First Page : 1267
Last Page : 1277
Authors : Stanton JL, Gruenfeld N, Babiarz JE, Ackerman MH, Friedmann RC, Yuan AM, Macchia W.
Abstract : The synthesis of N-(3-mercaptopropionyl)-N-arylglycines (14a-x),- N-arylalanines (15a,b),-N-cycloalkylglycines (16a-k), and -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids (17a-d), -1,2,3,4-tetrahydroquinoline-2-carboxylic acids (18a-f), and -indoline-2-carboxylic acids (19a-k) is described. In vitro inhibition of angiotensin converting enzyme (ACE) is reported for each compound, and the structure--activity relationship for each series is discussed. The in vivo inhibition of ACE and antihypertensive effects of representative compounds from each series are discussed. The most potent compound, 19d, had an in vitro ACE IC50 of 2.6 X 10(-9) M and lowered blood pressure in spontaneous hypertensive rats 85 mm at a dose of 10 mg/kg po.
|
% Inhibition of angiotensin-I induced pressor response in normotensive rats after intravenous dosing of 0.05 umol/kg
|
Rattus norvegicus
|
18.0
%
|
|
Journal : J. Med. Chem.
Title : Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines.
Year : 1988
Volume : 31
Issue : 6
First Page : 1148
Last Page : 1160
Authors : Krapcho J, Turk C, Cushman DW, Powell JR, DeForrest JM, Spitzmiller ER, Karanewsky DS, Duggan M, Rovnyak G, Schwartz J.
Abstract : Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.
|
% Inhibition of angiotensin-I induced pressor response in normotensive rats after intravenous dosing of 0.15 umol/kg
|
Rattus norvegicus
|
66.0
%
|
|
Journal : J. Med. Chem.
Title : Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines.
Year : 1988
Volume : 31
Issue : 6
First Page : 1148
Last Page : 1160
Authors : Krapcho J, Turk C, Cushman DW, Powell JR, DeForrest JM, Spitzmiller ER, Karanewsky DS, Duggan M, Rovnyak G, Schwartz J.
Abstract : Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.
|
% Inhibition of angiotensin-I induced pressor response in normotensive rats after intravenous dosing of 0.5 umol/kg
|
Rattus norvegicus
|
87.0
%
|
|
Journal : J. Med. Chem.
Title : Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines.
Year : 1988
Volume : 31
Issue : 6
First Page : 1148
Last Page : 1160
Authors : Krapcho J, Turk C, Cushman DW, Powell JR, DeForrest JM, Spitzmiller ER, Karanewsky DS, Duggan M, Rovnyak G, Schwartz J.
Abstract : Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.
|
% Inhibition of angiotensin-I induced pressor response in normotensive rats after intravenous dosing of 1.5 umol/kg
|
Rattus norvegicus
|
91.0
%
|
|
Journal : J. Med. Chem.
Title : Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines.
Year : 1988
Volume : 31
Issue : 6
First Page : 1148
Last Page : 1160
Authors : Krapcho J, Turk C, Cushman DW, Powell JR, DeForrest JM, Spitzmiller ER, Karanewsky DS, Duggan M, Rovnyak G, Schwartz J.
Abstract : Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.
|
% Inhibition of angiotensin-I induced pressor response in normotensive rats after peroral dosing of 0.5 umol/kg
|
Rattus norvegicus
|
42.0
%
|
|
Journal : J. Med. Chem.
Title : Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines.
Year : 1988
Volume : 31
Issue : 6
First Page : 1148
Last Page : 1160
Authors : Krapcho J, Turk C, Cushman DW, Powell JR, DeForrest JM, Spitzmiller ER, Karanewsky DS, Duggan M, Rovnyak G, Schwartz J.
Abstract : Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.
|
% Inhibition of angiotensin-I induced pressor response in normotensive rats after peroral dosing of 1.5 umol/kg
|
Rattus norvegicus
|
61.0
%
|
|
Journal : J. Med. Chem.
Title : Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines.
Year : 1988
Volume : 31
Issue : 6
First Page : 1148
Last Page : 1160
Authors : Krapcho J, Turk C, Cushman DW, Powell JR, DeForrest JM, Spitzmiller ER, Karanewsky DS, Duggan M, Rovnyak G, Schwartz J.
Abstract : Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.
|
% Inhibition of angiotensin-I induced pressor response in normotensive rats after peroral dosing of 15 umol/kg
|
Rattus norvegicus
|
78.0
%
|
|
Journal : J. Med. Chem.
Title : Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines.
Year : 1988
Volume : 31
Issue : 6
First Page : 1148
Last Page : 1160
Authors : Krapcho J, Turk C, Cushman DW, Powell JR, DeForrest JM, Spitzmiller ER, Karanewsky DS, Duggan M, Rovnyak G, Schwartz J.
Abstract : Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.
|
% Inhibition of angiotensin-I induced pressor response in normotensive rats after peroral dosing of 5 umol/kg
|
Rattus norvegicus
|
79.0
%
|
|
Journal : J. Med. Chem.
Title : Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines.
Year : 1988
Volume : 31
Issue : 6
First Page : 1148
Last Page : 1160
Authors : Krapcho J, Turk C, Cushman DW, Powell JR, DeForrest JM, Spitzmiller ER, Karanewsky DS, Duggan M, Rovnyak G, Schwartz J.
Abstract : Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.
|
% Inhibition of angiotensin-I induced pressor response in normotensive rats after peroral dosing of 50 umol/kg
|
Rattus norvegicus
|
93.0
%
|
|
Journal : J. Med. Chem.
Title : Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines.
Year : 1988
Volume : 31
Issue : 6
First Page : 1148
Last Page : 1160
Authors : Krapcho J, Turk C, Cushman DW, Powell JR, DeForrest JM, Spitzmiller ER, Karanewsky DS, Duggan M, Rovnyak G, Schwartz J.
Abstract : Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.
|
Inhibition of blood pressure increase produced by iv injection of angiotensin I in conscious normotensive rats at a dose of 30 mg/kg
|
Rattus norvegicus
|
69.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of the potent angiotensin converting enzyme inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline: effect of changes at positions 2 and 5 of the hexanoic acid portion.
Year : 1982
Volume : 25
Issue : 11
First Page : 1292
Last Page : 1299
Authors : Almquist RG, Crase J, Jennings-White C, Meyer RF, Hoefle ML, Smith RD, Essenburg AD, Kaplan HR.
Abstract : Several derivatives of the potent angiotensin converting enzyme inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline (1) were synthesized and tested for converting enzyme inhibition activity and blood pressure lowering effects in rats. One compound, 5(S)-benzamido-2(R)-methyl-4-oxo-6-phenylhexanoyl-L-proline (2a), had and I50 against angiotensin converting enzyme of 1.0 x 10(-9) M and is the most potent inhibitor prepared thus far in this class of compounds. Testing of 2a orally at 30 mg/kg for inhibition of the angiotensin I induced blood pressure increase in conscious normotensive rats gave 100% inhibition that required 143 min before the angiotensin I blood pressure response returned to 70% of the pretreatment control response. In the conscious renal hypertensive rat, 2a given orally at a dose of 3 mg/kg caused a lowering of blood pressure that reached its maximum of 40 mmHg 8 h following drug administration.
|
Inhibition of blood pressure increase produced by iv injection of angiotensin I in conscious normotensive rats at a dose of 3 mg/kg
|
Rattus norvegicus
|
95.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of the potent angiotensin converting enzyme inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline: effect of changes at positions 2 and 5 of the hexanoic acid portion.
Year : 1982
Volume : 25
Issue : 11
First Page : 1292
Last Page : 1299
Authors : Almquist RG, Crase J, Jennings-White C, Meyer RF, Hoefle ML, Smith RD, Essenburg AD, Kaplan HR.
Abstract : Several derivatives of the potent angiotensin converting enzyme inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline (1) were synthesized and tested for converting enzyme inhibition activity and blood pressure lowering effects in rats. One compound, 5(S)-benzamido-2(R)-methyl-4-oxo-6-phenylhexanoyl-L-proline (2a), had and I50 against angiotensin converting enzyme of 1.0 x 10(-9) M and is the most potent inhibitor prepared thus far in this class of compounds. Testing of 2a orally at 30 mg/kg for inhibition of the angiotensin I induced blood pressure increase in conscious normotensive rats gave 100% inhibition that required 143 min before the angiotensin I blood pressure response returned to 70% of the pretreatment control response. In the conscious renal hypertensive rat, 2a given orally at a dose of 3 mg/kg caused a lowering of blood pressure that reached its maximum of 40 mmHg 8 h following drug administration.
|
In vivo percent inhibition of angiotensin I pressor response 15 min after 1 mg/kg, iv administration in spontaneously hypertensive rat (SHR)
|
Rattus norvegicus
|
90.0
%
|
|
Journal : J. Med. Chem.
Title : Angiotensin converting enzyme inhibitors: 1-glutarylindoline-2-carboxylic acids derivatives.
Year : 1983
Volume : 26
Issue : 9
First Page : 1277
Last Page : 1282
Authors : Gruenfeld N, Stanton JL, Yuan AM, Ebetino FH, Browne LJ, Gude C, Huebner CF.
Abstract : The preparation of a series of 1-glutarylindoline-2(S)-carboxylic acid derivatives, 6a-v and 21a-c, is described. The above compounds were tested for inhibition of angiotensin converting enzyme. The structure-activity relationship of the series is also discussed. Compound 6u, the most potent member of the series, had an in vitro IC50 of 4.8 X 10(-9) M. Compound 6v, an ethyl ester of 6u, lowered blood pressure 70 mm in spontaneous hypertensive rats at an oral dose of 30 mg/kg.
|
Percent inhibition of angiotensin I pressor response 15 min after 0.3 mg/kg, iv administration in SHR
|
Rattus norvegicus
|
70.0
%
|
|
Journal : J. Med. Chem.
Title : Angiotensin converting enzyme inhibitors: 1-glutarylindoline-2-carboxylic acids derivatives.
Year : 1983
Volume : 26
Issue : 9
First Page : 1277
Last Page : 1282
Authors : Gruenfeld N, Stanton JL, Yuan AM, Ebetino FH, Browne LJ, Gude C, Huebner CF.
Abstract : The preparation of a series of 1-glutarylindoline-2(S)-carboxylic acid derivatives, 6a-v and 21a-c, is described. The above compounds were tested for inhibition of angiotensin converting enzyme. The structure-activity relationship of the series is also discussed. Compound 6u, the most potent member of the series, had an in vitro IC50 of 4.8 X 10(-9) M. Compound 6v, an ethyl ester of 6u, lowered blood pressure 70 mm in spontaneous hypertensive rats at an oral dose of 30 mg/kg.
|
% Inhibition of angiotensin-I induced pressor response in normotensive rats after intravenous dosing of 5 umol/kg
|
Rattus norvegicus
|
93.0
%
|
|
Journal : J. Med. Chem.
Title : Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines.
Year : 1988
Volume : 31
Issue : 6
First Page : 1148
Last Page : 1160
Authors : Krapcho J, Turk C, Cushman DW, Powell JR, DeForrest JM, Spitzmiller ER, Karanewsky DS, Duggan M, Rovnyak G, Schwartz J.
Abstract : Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.
|
Antihypertensive activity against human renin
|
Homo sapiens
|
1.7
nM
|
|
Journal : J. Med. Chem.
Title : Inhibition of the renin-angiotensin system. A new approach to the therapy of hypertension.
Year : 1981
Volume : 24
Issue : 4
First Page : 355
Last Page : 361
Authors : Ondetti MA, Cushman DW.
|
Inhibitory activity against thrombin
|
None
|
48.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Oxyguanidines. Part 2: Discovery of a novel orally active thrombin inhibitor through structure-based drug design and parallel synthesis.
Year : 2004
Volume : 14
Issue : 14
First Page : 3727
Last Page : 3731
Authors : Lu T, Markotan T, Coppo F, Tomczuk B, Crysler C, Eisennagel S, Spurlino J, Gremminger L, Soll RM, Giardino EC, Bone R.
Abstract : Through structure-based drug design and parallel synthesis, we have discovered a novel series of nonpeptidic phenyl-based thrombin inhibitors using oxyguanidines as guanidine bioisosteres. These compounds have been found to be highly potent, highly selective, and orally bioavailable.
|
Enzyme kinetic inhibition constant against tripeptide, Hip-His-Leu as substrate
|
None
|
71.5
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of a ketomethylene analogue of a tripeptide inhibitor of angiotensin converting enzyme.
Year : 1980
Volume : 23
Issue : 12
First Page : 1392
Last Page : 1398
Authors : Almquist RG, Chao WR, Ellis ME, Johnson HL.
Abstract : An analogue of a tripeptide inhibitor of angiotensin converting enzyme, Bz-Phe-Gly-Pro, has been synthesized in which the amide bond connecting phenylalanine and glycine has been replaced by a ketomethylene group. This nonpeptide analogue, 20, shows more potent converting enzyme inhibiting activity, I50 = 0.07 microM, than Bz-Phe-Gly-Pro, I50 = 9.4 microM, or than the orally active D-3-mercapto-2-methylpropanoyl-L-proline (captopril, 1), I50 = 0.30 microM. Compound 20 has a Ki of 1.06 X 10(-7) and either competitive or noncompetitive enzyme kinetics depending on what substrate is used in the converting enzyme assay. In tests for inhibition of angiotensin I induced contractions in the guinea pig ileum, 20 has one-tenth the activity of 1.
|
Inhibitory concentration against angiotensin I converting enzyme
|
Homo sapiens
|
23.0
nM
|
|
Journal : J. Med. Chem.
Title : Designed multiple ligands. An emerging drug discovery paradigm.
Year : 2005
Volume : 48
Issue : 21
First Page : 6523
Last Page : 6543
Authors : Morphy R, Rankovic Z.
|
Inhibition of ACE
|
None
|
7.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of ACE pharmacophore in the phosphonopeptide metabolite K-26.
Year : 2008
Volume : 18
Issue : 10
First Page : 3068
Last Page : 3071
Authors : Ntai I, Bachmann BO.
Abstract : The naturally occurring phosphonotripeptide K-26 is a potent angiotensin converting enzyme (ACE) inhibitor containing an alpha-amino phosphonic acid analogue of tyrosine. Previous studies have demonstrated that canonical peptide analogues of K-26 are micromolar inhibitors of ACE. To ascertain the structure-activity relationships in this class of ACE inhibitory natural products, K-26 and eight analogues were chemically synthesized and evaluated. Phosphonyl substitution was found to be the critical determinant of activity, resulting in a 1500-fold increase in ACE inhibition versus carboxyl analogues. Secondarily, the absolute configuration of the terminal alpha-amino phosphonate and N-acetylation were found to significantly modulate ACE inhibitory activity.
|
Antihypertensive activity in spontaneously hypertensive rat assessed as inhibition of angiotensin 1-induced vasopressive response at 0.04 mg/kg, iv after 10 mins
|
Rattus norvegicus
|
10.0
%
|
|
Journal : J. Nat. Prod.
Title : Inhibition of angiotensin-I-converting enzyme by tetrahydroxyxanthones isolated from Tripterospermum lanceolatum.
Year : 1992
Volume : 55
Issue : 5
First Page : 691
Last Page : 695
Authors : Chen CH, Lin JY, Lin CN, Hsu SY.
Abstract : Five tetrahydroxyxanthones, 3,4,6,7-tetrahydroxyxanthone [1], 1,3,5,6-tetrahydroxyxanthone [2], 3,4,5,6-tetrahydroxyxanthone [3], 1,3,6,7-tetrahydroxyxanthone [4], and 2,3,6,7-tetrahydroxyxanthone [5] isolated from Tripterospermum lanceolatum inhibited angiotensin-I-converting-enzyme activity in a dose-dependent manner. The mode of inhibition of the tetrahydroxyxanthones (THXs) was found to be competitive inhibition. When the tetrahydroxy groups of THXs were blocked with acetyl groups, the angiotensin-I-converting-enzyme inhibitory activity was abolished, suggesting that the tetrahydroxy groups are indispensible for the inhibitory activity.
|
Antihypertensive activity in spontaneously hypertensive rat assessed as inhibition of angiotensin 1-induced vasopressive response at 0.4 mg/kg, iv after 10 mins
|
Rattus norvegicus
|
78.5
%
|
|
Journal : J. Nat. Prod.
Title : Inhibition of angiotensin-I-converting enzyme by tetrahydroxyxanthones isolated from Tripterospermum lanceolatum.
Year : 1992
Volume : 55
Issue : 5
First Page : 691
Last Page : 695
Authors : Chen CH, Lin JY, Lin CN, Hsu SY.
Abstract : Five tetrahydroxyxanthones, 3,4,6,7-tetrahydroxyxanthone [1], 1,3,5,6-tetrahydroxyxanthone [2], 3,4,5,6-tetrahydroxyxanthone [3], 1,3,6,7-tetrahydroxyxanthone [4], and 2,3,6,7-tetrahydroxyxanthone [5] isolated from Tripterospermum lanceolatum inhibited angiotensin-I-converting-enzyme activity in a dose-dependent manner. The mode of inhibition of the tetrahydroxyxanthones (THXs) was found to be competitive inhibition. When the tetrahydroxy groups of THXs were blocked with acetyl groups, the angiotensin-I-converting-enzyme inhibitory activity was abolished, suggesting that the tetrahydroxy groups are indispensible for the inhibitory activity.
|
Antihypertensive activity in spontaneously hypertensive rat assessed as inhibition of angiotensin 1-induced vasopressive response at 0.04 mg/kg, iv after 20 mins
|
Rattus norvegicus
|
0.0
%
|
|
Journal : J. Nat. Prod.
Title : Inhibition of angiotensin-I-converting enzyme by tetrahydroxyxanthones isolated from Tripterospermum lanceolatum.
Year : 1992
Volume : 55
Issue : 5
First Page : 691
Last Page : 695
Authors : Chen CH, Lin JY, Lin CN, Hsu SY.
Abstract : Five tetrahydroxyxanthones, 3,4,6,7-tetrahydroxyxanthone [1], 1,3,5,6-tetrahydroxyxanthone [2], 3,4,5,6-tetrahydroxyxanthone [3], 1,3,6,7-tetrahydroxyxanthone [4], and 2,3,6,7-tetrahydroxyxanthone [5] isolated from Tripterospermum lanceolatum inhibited angiotensin-I-converting-enzyme activity in a dose-dependent manner. The mode of inhibition of the tetrahydroxyxanthones (THXs) was found to be competitive inhibition. When the tetrahydroxy groups of THXs were blocked with acetyl groups, the angiotensin-I-converting-enzyme inhibitory activity was abolished, suggesting that the tetrahydroxy groups are indispensible for the inhibitory activity.
|
Antihypertensive activity in spontaneously hypertensive rat assessed as inhibition of angiotensin 1-induced vasopressive response at 0.4 mg/kg, iv after 20 mins
|
Rattus norvegicus
|
66.6
%
|
|
Journal : J. Nat. Prod.
Title : Inhibition of angiotensin-I-converting enzyme by tetrahydroxyxanthones isolated from Tripterospermum lanceolatum.
Year : 1992
Volume : 55
Issue : 5
First Page : 691
Last Page : 695
Authors : Chen CH, Lin JY, Lin CN, Hsu SY.
Abstract : Five tetrahydroxyxanthones, 3,4,6,7-tetrahydroxyxanthone [1], 1,3,5,6-tetrahydroxyxanthone [2], 3,4,5,6-tetrahydroxyxanthone [3], 1,3,6,7-tetrahydroxyxanthone [4], and 2,3,6,7-tetrahydroxyxanthone [5] isolated from Tripterospermum lanceolatum inhibited angiotensin-I-converting-enzyme activity in a dose-dependent manner. The mode of inhibition of the tetrahydroxyxanthones (THXs) was found to be competitive inhibition. When the tetrahydroxy groups of THXs were blocked with acetyl groups, the angiotensin-I-converting-enzyme inhibitory activity was abolished, suggesting that the tetrahydroxy groups are indispensible for the inhibitory activity.
|
Antihypertensive activity in spontaneously hypertensive rat assessed as inhibition of angiotensin 1-induced vasopressive response at 0.04 mg/kg, iv after 30 mins
|
Rattus norvegicus
|
0.0
%
|
|
Journal : J. Nat. Prod.
Title : Inhibition of angiotensin-I-converting enzyme by tetrahydroxyxanthones isolated from Tripterospermum lanceolatum.
Year : 1992
Volume : 55
Issue : 5
First Page : 691
Last Page : 695
Authors : Chen CH, Lin JY, Lin CN, Hsu SY.
Abstract : Five tetrahydroxyxanthones, 3,4,6,7-tetrahydroxyxanthone [1], 1,3,5,6-tetrahydroxyxanthone [2], 3,4,5,6-tetrahydroxyxanthone [3], 1,3,6,7-tetrahydroxyxanthone [4], and 2,3,6,7-tetrahydroxyxanthone [5] isolated from Tripterospermum lanceolatum inhibited angiotensin-I-converting-enzyme activity in a dose-dependent manner. The mode of inhibition of the tetrahydroxyxanthones (THXs) was found to be competitive inhibition. When the tetrahydroxy groups of THXs were blocked with acetyl groups, the angiotensin-I-converting-enzyme inhibitory activity was abolished, suggesting that the tetrahydroxy groups are indispensible for the inhibitory activity.
|
Antihypertensive activity in spontaneously hypertensive rat assessed as inhibition of angiotensin 1-induced vasopressive response at 0.4 mg/kg, iv after 30 mins
|
Rattus norvegicus
|
45.5
%
|
|
Journal : J. Nat. Prod.
Title : Inhibition of angiotensin-I-converting enzyme by tetrahydroxyxanthones isolated from Tripterospermum lanceolatum.
Year : 1992
Volume : 55
Issue : 5
First Page : 691
Last Page : 695
Authors : Chen CH, Lin JY, Lin CN, Hsu SY.
Abstract : Five tetrahydroxyxanthones, 3,4,6,7-tetrahydroxyxanthone [1], 1,3,5,6-tetrahydroxyxanthone [2], 3,4,5,6-tetrahydroxyxanthone [3], 1,3,6,7-tetrahydroxyxanthone [4], and 2,3,6,7-tetrahydroxyxanthone [5] isolated from Tripterospermum lanceolatum inhibited angiotensin-I-converting-enzyme activity in a dose-dependent manner. The mode of inhibition of the tetrahydroxyxanthones (THXs) was found to be competitive inhibition. When the tetrahydroxy groups of THXs were blocked with acetyl groups, the angiotensin-I-converting-enzyme inhibitory activity was abolished, suggesting that the tetrahydroxy groups are indispensible for the inhibitory activity.
|
Inhibition of ACE by fluorometric assay
|
None
|
5.0
nM
|
|
Journal : J. Nat. Prod.
Title : Chemical and pharmaceutical studies on medicinal plants in Paraguay. Geraniin, an angiotensin-converting enzyme inhibitor from "paraparai mi," Phyllanthus niruri.
Year : 1988
Volume : 51
Issue : 2
First Page : 357
Last Page : 359
Authors : Ueno H, Horie S, Nishi Y, Shogawa H, Kawasaki M, Suzuki S, Hayashi T, Arisawa M, Shimizu M, Yoshizaki M.
|
Inhibition of human ACE
|
Homo sapiens
|
0.63
nM
|
|
Journal : J. Med. Chem.
Title : Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity.
Year : 2008
Volume : 51
Issue : 14
First Page : 4150
Last Page : 4169
Authors : Grice CA, Tays KL, Savall BM, Wei J, Butler CR, Axe FU, Bembenek SD, Fourie AM, Dunford PJ, Lundeen K, Coles F, Xue X, Riley JP, Williams KN, Karlsson L, Edwards JP.
Abstract : LTA 4H is a ubiquitously distributed 69 kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA 4H stereospecifically catalyzes the transformation of the unstable epoxide LTA 4 to the diol LTB 4, a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, and T cells. Inhibiting the formation of LTB 4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease (IBD), asthma, and atherosclerosis. We developed a pharmacophore model using a known inhibitor manually docked into the active site of LTA 4H to identify a subset of compounds for screening. From this work we identified a series of benzoxazole, benzthiazole, and benzimidazole inhibitors. SAR studies resulted in the identification of several potent inhibitors with an appropriate cross-reactivity profile and excellent PK/PD properties. Our efforts focused on further profiling JNJ 27265732, which showed encouraging efficacy in a disease model relevant to IBD.
|
Inhibition of guinea pig lung leukotriene A4 hydrolase at 1 mM
|
Cavia porcellus
|
59.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of N-mercaptoacylproline and N-mercaptoacylthiazolidine-4-carboxylic acid derivatives as leukotriene A4 hydrolase inhibitors.
Year : 2008
Volume : 18
Issue : 16
First Page : 4529
Last Page : 4532
Authors : Enomoto H, Morikawa Y, Miyake Y, Tsuji F, Mizuchi M, Suhara H, Fujimura K, Horiuchi M, Ban M.
Abstract : We studied the synthetic modification of structurally similar N-mercaptoacyl-L-proline and (4R)-N-mercaptoacylthiazolidine-4-carboxylic acid to obtain potent leukotriene A(4) (LTA(4)) hydrolase inhibitors. An N-mercaptoacyl group, (2S)-3-mercapto-2-methylpropionyl group, was effective for both scaffolds. Additional introduction of a large substituent such as 4-isopropylbenzylthio (3f), 4-tert-butylbenzylthio (3l) or 4-cyclohexylbenzylthio group (3m) with (S)-configuration at the C(4) position of proline yielded much more potent LTA(4) hydrolase inhibitors (IC(50); 52, 31, and 34 nM, respectively) than captopril (IC(50); 630,000 nM).
|
Inhibition of ACE
|
None
|
23.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of N-mercaptoacylproline and N-mercaptoacylthiazolidine-4-carboxylic acid derivatives as leukotriene A4 hydrolase inhibitors.
Year : 2008
Volume : 18
Issue : 16
First Page : 4529
Last Page : 4532
Authors : Enomoto H, Morikawa Y, Miyake Y, Tsuji F, Mizuchi M, Suhara H, Fujimura K, Horiuchi M, Ban M.
Abstract : We studied the synthetic modification of structurally similar N-mercaptoacyl-L-proline and (4R)-N-mercaptoacylthiazolidine-4-carboxylic acid to obtain potent leukotriene A(4) (LTA(4)) hydrolase inhibitors. An N-mercaptoacyl group, (2S)-3-mercapto-2-methylpropionyl group, was effective for both scaffolds. Additional introduction of a large substituent such as 4-isopropylbenzylthio (3f), 4-tert-butylbenzylthio (3l) or 4-cyclohexylbenzylthio group (3m) with (S)-configuration at the C(4) position of proline yielded much more potent LTA(4) hydrolase inhibitors (IC(50); 52, 31, and 34 nM, respectively) than captopril (IC(50); 630,000 nM).
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
0.3
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Inhibition of ACE at 0.01 mg/ml
|
None
|
97.7
%
|
|
Journal : J. Nat. Prod.
Title : Three cyclooctapeptides and one glycoside from Microtoena prainiana.
Year : 2004
Volume : 67
Issue : 6
First Page : 978
Last Page : 982
Authors : Li CQ, Li BG, Qi HY, Li QL, Wang FP, Zhang GL.
Abstract : Three new cyclic octapeptides, microtoenins A-C (1-3), and a new glycoside, 3'''-O-methylcrenatoside (4), along with several known compounds, were isolated from the ethanolic extract of the stems of Microtoena prainiana. Their structures were determined by spectral and chemical evidence. At a concentration of 0.01 mg/mL, 3'''-O-methylcrenatoside (4), crenatoside (5), and isocrenatoside (6) inhibited angiotensin converting enzyme (ACE) activity by more than 30%.
|
Inhibition of human recombinant ACE by fluorimetry
|
Homo sapiens
|
0.12
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and enzymatic evaluation of novel partially fluorinated thiol dual ACE/NEP inhibitors.
Year : 2009
Volume : 19
Issue : 16
First Page : 4715
Last Page : 4719
Authors : Olimpieri F, Tambaro S, Fustero S, Lazzari P, Sanchez-Roselló M, Pani L, Volonterio A, Zanda M.
Abstract : A novel family of peptidomimetics incorporating fluoroalkyl groups, mainly a trifluoromethyl, in alpha-position to a zinc(II)-binding thiol function, was synthesized in solution as well as in solid-phase. These compounds showed inhibitory potency in the nanomolar range against both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), whereas no inhibition of endothelin-converting enzyme-1 (ECE-1) was observed. The trifluoromethyl-derivatives were more potent than the parent unfluorinated analogues in the case of ACE, and less potent in the case of NEP.
|
Antioxidant activity assessed as protection against hemin-induced erythrocytes hemolysis at 0.6 uM
|
None
|
80.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Captopril and 6-mercaptopurine: whose SH possesses higher antioxidant ability?
Year : 2009
Volume : 44
Issue : 12
First Page : 4841
Last Page : 4847
Authors : Li GX, Liu ZQ.
Abstract : Antioxidant capacities of captopril (CAP), 6-mercaptopurine (6-MP) and 9-(beta-D-ribofuranosyl)-6-mercaptopurine (6-MPR) were investigated by interacting them with 2,2'-diphenyl-1-picrylhydrazyl (DPPH), galvinoxyl radical, and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cation radical (ABTS(+)(*)), and by protecting DNA and erythrocyte against 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH) induced oxidation. It was found that CAP possessed the highest ability to donate the hydrogen atom in -SH to DPPH and galvinoxyl, while 6-MPR had the strongest ability to reduce ABTS(+)(*). In the process of protecting DNA and erythrocytes against AAPH-induced oxidation, CAP can trap 0.5 and 1.3 radicals, 6-MP can trap 0.6 and 2.2, and 6-MPR can trap 1.0 and 3.0 radicals, respectively. CAP can also protect erythrocytes against hemin-induced hemolysis.
|
DRUGMATRIX: Peptidase, Angiotensin Converting Enzyme enzyme inhibition (substrate: FAPGG)
|
Oryctolagus cuniculus
|
130.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
18.6
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
4.0
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
39.1
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of mouse Ido2 transfected in HEK293T cells using L-tryptophan as substrate assessed as kynurenine formation at 20 uM after 45 mins by spectrophotometric analysis relative to control
|
Mus musculus
|
55.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of selective inhibitors of indoleamine 2,3-dioxygenase 2.
Year : 2012
Volume : 22
Issue : 24
First Page : 7641
Last Page : 7646
Authors : Bakmiwewa SM, Fatokun AA, Tran A, Payne RJ, Hunt NH, Ball HJ.
Abstract : The kynurenine pathway is responsible for the breakdown of the majority of the essential amino acid, tryptophan (Trp). The first and rate-limiting step of the kynurenine pathway can be independently catalysed by tryptophan 2,3-dioxygenase (Tdo2), indoleamine 2,3-dioxygenase 1 (Ido1) or indoleamine 2,3-dioxygenase 2 (Ido2). Tdo2 or Ido1 enzymatic activity has been implicated in a number of actions of the kynurenine pathway, including immune evasion by tumors. IDO2 is expressed in several human pancreatic cancer cell lines, suggesting it also may play a role in tumorigenesis. Although Ido2 was originally suggested to be a target of the chemotherapeutic agent dextro-1-methyl-tryptophan, subsequent studies suggest this compound does not inhibit Ido2 activity. The development of selective Ido2 inhibitors could provide valuable tools for investigating its activity in tumor development and normal physiology. In this study, a library of Food and Drug Administration-approved drugs was screened for inhibition of mouse Ido2 enzymatic activity. A number of candidates were identified and IC(50) values of each compound for Ido1 and Ido2 were estimated. The Ido2 inhibitors were also tested for inhibition of Tdo2 activity. Our results showed that compounds from a class of drugs used to inhibit proton pumps were the most potent and selective Ido2 inhibitors identified in the library screen. These included tenatoprazole, which exhibited an IC(50) value of 1.8μM for Ido2 with no inhibition of Ido1 or Tdo2 activity detected at a concentration of 100μM tenatoprazole. These highly-selective Ido2 inhibitors will be useful for defining the distinct biological roles of the three Trp-catabolizing enzymes.
|
Antihypertensive activity in Rattus norvegicus Sprague-Dawley (rat) assessed as inhibition of angiotensin-1-induced increase in blood pressure at 10 ug/kg, iv administered 5 min before angiotensin-1 challenge
|
Rattus norvegicus
|
60.0
%
|
|
Journal : Med Chem Res
Title : Synthesis of N-[3-(acetylthio)alkanoyl] and N-[3-mercaptoalkanoyl]-4-(s)-(phenylmethyl) pyroglutamic acids and prolines as potent ACE inhibitors
Year : 2009
Volume : 18
Issue : 7
First Page : 566
Last Page : 578
Authors : Panday SK, Dikshit M, Dikshit DK
|
Inhibition of Rattus norvegicus (rat) serum acetylcholinesterase at 10 nM
|
Rattus norvegicus
|
56.5
%
|
|
Journal : Med Chem Res
Title : Synthesis of N-[3-(acetylthio)alkanoyl] and N-[3-mercaptoalkanoyl]-4-(s)-(phenylmethyl) pyroglutamic acids and prolines as potent ACE inhibitors
Year : 2009
Volume : 18
Issue : 7
First Page : 566
Last Page : 578
Authors : Panday SK, Dikshit M, Dikshit DK
|
Inhibition of human recombinant MMP-2 using Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2.AcOH as substrate at 10 uM preincubated for 30 mins prior to substrate addition measured for 30 mins by fluorescence assay relative to control
|
Homo sapiens
|
10.0
%
|
|
Journal : J. Med. Chem.
Title : Investigating the selectivity of metalloenzyme inhibitors.
Year : 2013
Volume : 56
Issue : 20
First Page : 7997
Last Page : 8007
Authors : Day JA, Cohen SM.
Abstract : The inhibitory activity of a broad group of known metalloenzyme inhibitors against a panel of metalloenzymes was evaluated. Clinically approved inhibitors were selected as well as several other reported metalloprotein inhibitors in order to represent a broad range of metal binding groups (MBGs), including hydroxamic acid, carboxylate, hydroxypyridinonate, thiol, and N-hydroxyurea functional groups. A panel of metalloenzymes, including carbonic anhydrase (hCAII), several matrix metalloproteinases (MMPs), angiotensin converting enzyme (ACE), histone deacetylase (HDAC-2), and tyrosinase (TY), was selected based on their clinical importance for a range of pathologies. In addition, each inhibitor was evaluated for its ability to remove Fe(3+) from holo-transferrin to gauge the ability of the inhibitors to access Fe(3+) from a primary transport protein. The results show that the metalloenzyme inhibitors are quite selective for their intended targets, suggesting that despite their ability to bind metal ions, metalloprotein inhibitors are not prone to widespread off-target enzyme inhibition activity.
|
Inhibition of human recombinant ACE/CD143 somatic form using Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2.AcOH as substrate preincubated for 10 mins prior to substrate addition measured for 30 mins by spectrophotometric analysis
|
Homo sapiens
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : Investigating the selectivity of metalloenzyme inhibitors.
Year : 2013
Volume : 56
Issue : 20
First Page : 7997
Last Page : 8007
Authors : Day JA, Cohen SM.
Abstract : The inhibitory activity of a broad group of known metalloenzyme inhibitors against a panel of metalloenzymes was evaluated. Clinically approved inhibitors were selected as well as several other reported metalloprotein inhibitors in order to represent a broad range of metal binding groups (MBGs), including hydroxamic acid, carboxylate, hydroxypyridinonate, thiol, and N-hydroxyurea functional groups. A panel of metalloenzymes, including carbonic anhydrase (hCAII), several matrix metalloproteinases (MMPs), angiotensin converting enzyme (ACE), histone deacetylase (HDAC-2), and tyrosinase (TY), was selected based on their clinical importance for a range of pathologies. In addition, each inhibitor was evaluated for its ability to remove Fe(3+) from holo-transferrin to gauge the ability of the inhibitors to access Fe(3+) from a primary transport protein. The results show that the metalloenzyme inhibitors are quite selective for their intended targets, suggesting that despite their ability to bind metal ions, metalloprotein inhibitors are not prone to widespread off-target enzyme inhibition activity.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
167.02
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
105.18
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of COX-2 (unknown origin) using arachidonic acid as substrate assessed as formation of prostanoid products at 500 uM preincubated for 10 mins prior to substrate addition measured after 2 mins by Ellman's method relative to control
|
Homo sapiens
|
61.0
%
|
|
Journal : J. Med. Chem.
Title : Experimental confirmation of new drug-target interactions predicted by Drug Profile Matching.
Year : 2013
Volume : 56
Issue : 21
First Page : 8377
Last Page : 8388
Authors : Végner L, Peragovics Á, Tombor L, Jelinek B, Czobor P, Bender A, Simon Z, Málnási-Csizmadia A.
Abstract : We recently introduced Drug Profile Matching (DPM), a novel affinity fingerprinting-based in silico drug repositioning approach. DPM is able to quantitatively predict the complete effect profiles of compounds via probability scores. In the present work, in order to investigate the predictive power of DPM, three effect categories, namely, angiotensin-converting enzyme inhibitor, cyclooxygenase inhibitor, and dopamine agent, were selected and predictions were verified by literature analysis as well as experimentally. A total of 72% of the newly predicted and tested dopaminergic compounds were confirmed by tests on D1 and D2 expressing cell cultures. 33% and 23% of the ACE and COX inhibitory predictions were confirmed by in vitro tests, respectively. Dose-dependent inhibition curves were measured for seven drugs, and their inhibitory constants (Ki) were determined. Our study overall demonstrates that DPM is an effective approach to reveal novel drug-target pairs that may result in repositioning these drugs.
|
Inhibition of COX-1 (unknown origin) using arachidonic acid as substrate assessed as formation of prostanoid products at 500 uM preincubated for 10 mins prior to substrate addition measured after 2 mins by Ellman's method relative to control
|
Homo sapiens
|
48.0
%
|
|
Journal : J. Med. Chem.
Title : Experimental confirmation of new drug-target interactions predicted by Drug Profile Matching.
Year : 2013
Volume : 56
Issue : 21
First Page : 8377
Last Page : 8388
Authors : Végner L, Peragovics Á, Tombor L, Jelinek B, Czobor P, Bender A, Simon Z, Málnási-Csizmadia A.
Abstract : We recently introduced Drug Profile Matching (DPM), a novel affinity fingerprinting-based in silico drug repositioning approach. DPM is able to quantitatively predict the complete effect profiles of compounds via probability scores. In the present work, in order to investigate the predictive power of DPM, three effect categories, namely, angiotensin-converting enzyme inhibitor, cyclooxygenase inhibitor, and dopamine agent, were selected and predictions were verified by literature analysis as well as experimentally. A total of 72% of the newly predicted and tested dopaminergic compounds were confirmed by tests on D1 and D2 expressing cell cultures. 33% and 23% of the ACE and COX inhibitory predictions were confirmed by in vitro tests, respectively. Dose-dependent inhibition curves were measured for seven drugs, and their inhibitory constants (Ki) were determined. Our study overall demonstrates that DPM is an effective approach to reveal novel drug-target pairs that may result in repositioning these drugs.
|
Inhibition of ACE (unknown origin) assessed as 3-Hydroxybutyril-glycil-glycil-glycine conversion to 3-hydroxybutyric acid after 60 mins by WST assay
|
Homo sapiens
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Experimental confirmation of new drug-target interactions predicted by Drug Profile Matching.
Year : 2013
Volume : 56
Issue : 21
First Page : 8377
Last Page : 8388
Authors : Végner L, Peragovics Á, Tombor L, Jelinek B, Czobor P, Bender A, Simon Z, Málnási-Csizmadia A.
Abstract : We recently introduced Drug Profile Matching (DPM), a novel affinity fingerprinting-based in silico drug repositioning approach. DPM is able to quantitatively predict the complete effect profiles of compounds via probability scores. In the present work, in order to investigate the predictive power of DPM, three effect categories, namely, angiotensin-converting enzyme inhibitor, cyclooxygenase inhibitor, and dopamine agent, were selected and predictions were verified by literature analysis as well as experimentally. A total of 72% of the newly predicted and tested dopaminergic compounds were confirmed by tests on D1 and D2 expressing cell cultures. 33% and 23% of the ACE and COX inhibitory predictions were confirmed by in vitro tests, respectively. Dose-dependent inhibition curves were measured for seven drugs, and their inhibitory constants (Ki) were determined. Our study overall demonstrates that DPM is an effective approach to reveal novel drug-target pairs that may result in repositioning these drugs.
|
Inhibition of angiotensin-converting enzyme (unknown origin)
|
Homo sapiens
|
22.91
nM
|
|
Journal : MedChemComm
Title : Rational design of small modified peptides as ACE inhibitors
Year : 2012
Volume : 3
Issue : 10
First Page : 1290
Last Page : 1293
Authors : Silva DG, Freitas MP, da Cunha EFF, Ramalho TC, Nunes CA
|
Inhibition of human ACE-mediated amyloid beta hydrolysis
|
Homo sapiens
|
11.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-β hydrolysis.
Year : 2014
Volume : 79
First Page : 184
Last Page : 193
Authors : Charton J, Gauriot M, Guo Q, Hennuyer N, Marechal X, Dumont J, Hamdane M, Pottiez V, Landry V, Sperandio O, Flipo M, Buee L, Staels B, Leroux F, Tang WJ, Deprez B, Deprez-Poulain R.
Abstract : Insulin degrading enzyme (IDE) is a highly conserved zinc metalloprotease that is involved in the clearance of various physiologically peptides like amyloid-beta and insulin. This enzyme has been involved in the physiopathology of diabetes and Alzheimer's disease. We describe here a series of small molecules discovered by screening. Co-crystallization of the compounds with IDE revealed a binding both at the permanent exosite and at the discontinuous, conformational catalytic site. Preliminary structure-activity relationships are described. Selective inhibition of amyloid-beta degradation over insulin hydrolysis was possible. Neuroblastoma cells treated with the optimized compound display a dose-dependent increase in amyloid-beta levels.
|
Inhibition of ACE (unknown origin) using 3-Hydroxybutylyl-Gly-Gly-Gly substrate assessed as reduction in 3-Hyroxybutylic acid generation incubated for 1 hr by colorimetric assay
|
Homo sapiens
|
1.61
nM
|
|
Journal : J. Nat. Prod.
Title : Top-down Targeted Metabolomics Reveals a Sulfur-Containing Metabolite with Inhibitory Activity against Angiotensin-Converting Enzyme in Asparagus officinalis.
Year : 2015
Volume : 78
Issue : 5
First Page : 1179
Last Page : 1183
Authors : Nakabayashi R, Yang Z, Nishizawa T, Mori T, Saito K.
Abstract : The discovery of bioactive natural compounds containing sulfur, which is crucial for inhibitory activity against angiotensin-converting enzyme (ACE), is a challenging task in metabolomics. Herein, a new S-containing metabolite, asparaptine (1), was discovered in the spears of Asparagus officinalis by targeted metabolomics using mass spectrometry for S-containing metabolites. The contribution ratio (2.2%) to the IC50 value in the crude extract showed that asparaptine (1) is a new ACE inhibitor.
|
Reversible binding affinity to Pseudomonas aeruginosa 301-5473 metallo-beta-lactamase VIM-2 expressed in Escherichia coli BL21(DE3) measured for 15 secs by SPR analysis
|
Pseudomonas aeruginosa
|
0.025
/s
|
|
Reversible binding affinity to Pseudomonas aeruginosa 301-5473 metallo-beta-lactamase VIM-2 expressed in Escherichia coli BL21(DE3) measured for 15 secs by SPR analysis
|
Pseudomonas aeruginosa
|
600.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Novel Inhibitor Scaffolds against the Metallo-β-lactamase VIM-2 by Surface Plasmon Resonance (SPR) Based Fragment Screening.
Year : 2015
Volume : 58
Issue : 21
First Page : 8671
Last Page : 8682
Authors : Christopeit T, Carlsen TJ, Helland R, Leiros HK.
Abstract : Metallo-β-lactamase (MBL) inhibitors can restore the function of carbapenem antibiotics and therefore help to treat infections of antibiotic resistant bacteria. In this study, we report novel fragments inhibiting the clinically relevant MBL Verona integron-encoded metallo-β-lactamase (VIM-2). The fragments were identified from a library of 490 fragments using an orthogonal screening approach based on a surface plasmon resonance (SPR) based assay combined with an enzyme inhibition assay. The identified fragments showed IC50 values between 14 and 1500 μM and ligand efficiencies (LE) between 0.48 and 0.23 kcal/mol per heavy atom. For two of the identified fragments, crystal structures in complex with VIM-2 were obtained. The identified fragments represent novel inhibitor scaffolds and are good starting points for the design of potent MBL inhibitors. Furthermore, the established SPR based assay and the screening approach can be adapted to other MBLs and in this way improve the drug discovery process for this important class of drug targets.
|
Inhibition of recombinant human ACE at 1 uM using Mca-R-P-PG-F-S-A-F-K(Dnp)-OH as substrate measured every 2 mins for 8 mins by fluorescence assay
|
Homo sapiens
|
95.03
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of a potent angiotensin converting enzyme inhibitor via virtual screening.
Year : 2017
Volume : 27
Issue : 16
First Page : 3688
Last Page : 3692
Authors : Ke Z, Su Z, Zhang X, Cao Z, Ding Y, Cao L, Ding G, Wang Z, Liu H, Xiao W.
Abstract : Prompted by the prominent role of angiotensin converting enzyme (ACE) in hypertension, heart failures, myocardial infarction and diabetic nephropathy, we have attempted to discover novel ACE inhibitors through ligand-based virtual screening. Molecular docking method and rigorously validated model was utilized to search a natural compounds database. Finally, 36 compounds were randomly selected and subjected to in vitro ACE kinase inhibitory assay using fluorescence assays method. The results showed that three compounds (Licochalcone A, Echinatin and EGCG) have strong potential to be developed as a new class of ACE inhibitors. Further chemical modification via fragment modifications guided by structure and ligand-based computational methodologies can lead to discover better agents as potential clinical candidates.
|
Inhibition of Wistar rat plasma angiotensin 1-converting enzyme using H-hippuryl-His-Leu-OH as substrate after 20 mins by fluorescence assay
|
Rattus norvegicus
|
3.23
nM
|
|
Journal : Eur J Med Chem
Title : Structure-function studies of BPP-BrachyNH2 and synthetic analogues thereof with Angiotensin I-Converting Enzyme.
Year : 2017
Volume : 139
First Page : 401
Last Page : 411
Authors : Arcanjo DDR, Vasconcelos AG, Nascimento LA, Mafud AC, Plácido A, Alves MMM, Delerue-Matos C, Bemquerer MP, Vale N, Gomes P, Oliveira EB, Lima FCA, Mascarenhas YP, Carvalho FAA, Simonsen U, Ramos RM, Leite JRSA.
Abstract : The vasoactive proline-rich oligopeptide termed BPP-BrachyNH2 (H-WPPPKVSP-NH2) induces in vitro inhibitory activity of angiotensin I-converting enzyme (ACE) in rat blood serum. In the present study, the removal of N-terminal tryptophan or C-terminal proline from BPP-BrachyNH2 was investigated in order to predict which structural components are important or required for interaction with ACE. Furthermore, the toxicological profile was assessed by in silico prediction and in vitro MTT assay. Two BPP-BrachyNH2 analogues (des-Trp1-BPP-BrachyNH2 and des-Pro8-BPP-BrachyNH2) were synthesized, and in vitro and in silico ACE inhibitory activity and toxicological profile were assessed. The des-Trp1-BPP-BrachyNH2 and des-Pro8-BPP-BrachyNH2 were respectively 3.2- and 29.5-fold less active than the BPP-BrachyNH2-induced ACE inhibitory activity. Molecular Dynamic and Molecular Mechanics Poisson-Boltzmann Surface Area simulations (MM-PBSA) demonstrated that the ACE/BBP-BrachyNH2 complex showed lower binding and van der Wall energies than the ACE/des-Pro8-BPP-BrachyNH2 complex, therefore having better stability. The removal of the N-terminal tryptophan increased the in silico predicted toxicological effects and cytotoxicity when compared with BPP-BrachyNH2 or des-Pro8-BPP-BrachyNH2. Otherwise, des-Pro8-BPP-BrachyNH2 was 190-fold less cytotoxic than BPP-BrachyNH2. Thus, the removal of C-terminal proline residue was able to markedly decrease both the BPP-BrachyNH2-induced ACE inhibitory and cytotoxic effects assessed by in vitro and in silico approaches. In conclusion, the aminoacid sequence of BPP-BrachyNH2 is essential for its ACE inhibitory activity and associated with an acceptable toxicological profile. The perspective of the interactions of BPP-BrachyNH2 with ACE found in the present study can be used for development of drugs with differential therapeutic profile than current ACE inhibitors.
|
Inhibition of ACE (unknown origin) using hippuryl-L-histidyl-L-leucine as substrate preincubated with substrate for 30 mins followed by enzyme addition measured after 30 mins by LC/MS analysis
|
Homo sapiens
|
25.0
nM
|
|
Journal : J Nat Prod
Title : Metabolomics-Guided Discovery of Microginin Peptides from Cultures of the Cyanobacterium Microcystis aeruginosa.
Year : 2018
Volume : 81
Issue : 2
First Page : 349
Last Page : 355
Authors : Stewart AK, Ravindra R, Van Wagoner RM, Wright JLC.
Abstract : We report a mass-spectrometry-based metabolomics study of a laboratory-cultured strain of Microcystis aeruginosa (UTEX LB2385), which has led to the discovery of five peptides (1-5) belonging to the microginin class of linear cyanopeptides. The structures and configurations of these peptides were determined by spectroscopic analyses and chemical derivitization. The microginin peptides described herein are the first reported derivatives containing N-methyl methionine (1, 5) and N-methyl methionine sulfoxide (2-4). The two tripeptide microginin analogues (4, 5) identified represent the smallest members of this peptide family. Their angiotensin-converting enzyme (ACE) inhibitory activity was also investigated. Microginin 527 (4) was the most potent of the group, with an IC50 of 31 μM.
|
Inhibition of human ACE using Hip-His-Leu-OH as substrate after 1 hr by fluorimetric method
|
Homo sapiens
|
6.3
nM
|
|
Journal : J Med Chem
Title : Quest for Novel Chemical Entities through Incorporation of Silicon in Drug Scaffolds.
Year : 2018
Volume : 61
Issue : 9
First Page : 3779
Last Page : 3798
Authors : Ramesh R, Reddy DS.
Abstract : In order to optimize a lead molecule for further development, bioisosteric replacements are generally adopted as one of the strategies. Silicon appears to be the right choice as a carbon isostere because of the similarity in chemical properties. Silicon can be strategically introduced in a molecule to modulate its druglike properties, providing medicinal chemists with an unconventional strategy for replacing a carbon atom. Silicon can also be introduced to replace other heteroatoms and can act as a surrogate of functional groups such as olefin and amide as well. The present Perspective focuses on the opportunities that silicon incorporation offers in drug discovery, with an emphasis on case studies where introduction of silicon has created a benefit over its analog. We have tried to highlight all the recent developments in the field and briefly discuss the challenges associated with them.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
-7.06
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
4.92
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
9.36
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
11.48
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
30.0
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
2.59
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
1.67
%
|
|
|
IC50 for antiviral activity against SARS-CoV-2 in the Vero E6 cell line at 48 h by immunofluorescence-based assay (detecting the viral NP protein in the nucleus of the Vero E6 cells).
|
Chlorocebus sabaeus
|
389.05
nM
|
|
Journal : Nature
Title : A SARS-CoV-2 protein interaction map reveals targets for drug repurposing
Year : 2020
Authors : David E Gordon, Gwendolyn M Jang, Mehdi Bouhaddou, Jiewei Xu, Kirsten Obernier, Kris M White, Matthew J O'Meara, Veronica V Rezelj, Jeffrey Z Guo, Danielle L Swaney, et al
Abstract : The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
8.7
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of bacterial N-terminal His-tagged TEV protease site linked VIM-2 (27 to 266 amino acids) expressed in Escherichia coli Transetta (DE3) preincubated for 10 mins followed by FC5 fluorescent substrate addition by fluorescence assay
|
Bacteria
|
360.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Development of (1-(3'-Mercaptopropanamido)methyl)boronic Acid Derived Broad-Spectrum, Dual-Action Inhibitors of Metallo- and Serine-β-lactamases.
Year : 2019
Volume : 62
Issue : 15
First Page : 7160
Last Page : 7184
Authors : Wang YL, Liu S, Yu ZJ, Lei Y, Huang MY, Yan YH, Ma Q, Zheng Y, Deng H, Sun Y, Wu C, Yu Y, Chen Q, Wang Z, Wu Y, Li GB.
Abstract : The emergence and spread of bacterial pathogens acquired metallo-β-lactamase (MBL) and serine-β-lactamase (SBL) medicated β-lactam resistance gives rise to an urgent need for the development of new dual-action MBL/SBL inhibitors. Application of a pharmacophore fusion strategy led to the identification of (2'S)-(1-(3'-mercapto-2'-methylpropanamido)methyl)boronic acid (MS01) as a new dual-action inhibitor, which manifests broad-spectrum inhibition to representative MBL/SBL enzymes, including the widespread VIM-2 and KPC-2. Guided by the VIM-2:MS01 and KPC-2:MS01 complex structures, further structural optimization yielded new, more potent dual-action inhibitors. Selectivity studies indicated that the inhibitors had no apparent inhibition to human angiotensin-converting enzyme-2 and showed selectivity across serine hydrolyases in E. coli and human HEK293T cells labeled by the activity-based probe TAMRA-FP. Moreover, the inhibitors displayed potentiation of meropenem efficacy against MBL- or SBL-positive clinical isolates without apparent cytotoxicity. This work will aid efforts to develop new types of clinically useful dual-action inhibitors targeting MBL/SBL enzymes.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
10.43
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
28.3
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.27
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.17
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.17
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.27
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
