|
In vitro inhibition of collagen stimulated platelet aggregation in human whole blood
|
Homo sapiens
|
350.0
nM
|
|
Journal : J. Med. Chem.
Title : Cardiotonic agents. 9. Synthesis and biological evaluation of a series of (E)-4,5-dihydro-6-[2-[4-(1H-imidazol-1-yl)phenyl]ethenyl]-3 (2H)-pyridazinones: a novel class of compounds with positive inotropic, antithrombotic, and vasodilatory activities for the treatment of congestive heart failure.
Year : 1989
Volume : 32
Issue : 2
First Page : 342
Last Page : 350
Authors : Sircar I, Steffen RP, Bobowski G, Burke SE, Newton RS, Weishaar RE, Bristol JA, Evans DB.
Abstract : A novel series of analogues of (E)-4,5-dihydro-6-[2-[4-(1H-imidazol-1-yl) phenyl]ethenyl]-3(2H)-pyridazinone was synthesized as a variation on the imazodan series. The compounds were evaluated for (i) hemodynamic activity, (ii) cyclic AMP-phosphodiesterase inhibitory activity (human platelets and guinea pig heart tissue), and (iii) platelet aggregation inhibitory activity. The insertion of the ethenyl moiety between the phenyl and dihydropyridazinone rings produced novel compounds that retained the potent inotropic/vasodilator activity of the parent imazodan series and enhanced the platelet aggregation inhibitory potency. Compound 3d, the most potent in this series, demonstrated in vivo antithrombotic activity. The synthesis and the biological activity of these new pyridazinone analogues are reported.
|
In vitro inhibition of collagen stimulated platelet aggregation in human thrombocyte enriched plasma
|
Homo sapiens
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Cardiotonic agents. 9. Synthesis and biological evaluation of a series of (E)-4,5-dihydro-6-[2-[4-(1H-imidazol-1-yl)phenyl]ethenyl]-3 (2H)-pyridazinones: a novel class of compounds with positive inotropic, antithrombotic, and vasodilatory activities for the treatment of congestive heart failure.
Year : 1989
Volume : 32
Issue : 2
First Page : 342
Last Page : 350
Authors : Sircar I, Steffen RP, Bobowski G, Burke SE, Newton RS, Weishaar RE, Bristol JA, Evans DB.
Abstract : A novel series of analogues of (E)-4,5-dihydro-6-[2-[4-(1H-imidazol-1-yl) phenyl]ethenyl]-3(2H)-pyridazinone was synthesized as a variation on the imazodan series. The compounds were evaluated for (i) hemodynamic activity, (ii) cyclic AMP-phosphodiesterase inhibitory activity (human platelets and guinea pig heart tissue), and (iii) platelet aggregation inhibitory activity. The insertion of the ethenyl moiety between the phenyl and dihydropyridazinone rings produced novel compounds that retained the potent inotropic/vasodilator activity of the parent imazodan series and enhanced the platelet aggregation inhibitory potency. Compound 3d, the most potent in this series, demonstrated in vivo antithrombotic activity. The synthesis and the biological activity of these new pyridazinone analogues are reported.
|
Percentage inhibition of cAMP PDE in canine brain tissue
|
Canis lupus familiaris
|
34.0
%
|
|
Journal : J. Med. Chem.
Title : (Imidazolylphenyl)pyrrol-2-one inhibitors of cardiac cAMP phosphodiesterase.
Year : 1993
Volume : 36
Issue : 8
First Page : 1041
Last Page : 1047
Authors : Lampe JW, Chou YL, Hanna RG, Di Meo SV, Erhardt PW, Hagedorn AA, Ingebretsen WR, Cantor E.
Abstract : Seven 3-alkyl-4-aryl-1,5-dihydro-2H-pyrrol-2-ones were prepared as potential inhibitors of cardiac cAMP phosphodiesterase (PDE). The design of these compounds made use of rolipram, a known inhibitor of the brain cAMP PDE isozyme, as a lead structure and was guided by a model which describes the features required for potent inhibition of the cardiac isozyme. Syntheses for the new compounds are described, together with the results of theoretical and crystallographic studies aimed toward ascertaining their three-dimensional structures. The activities of these compounds as inhibitors of the cardiac and brain cAMP PDE isozymes and their positive inotropic activity in ferret papillary muscle are also reported. Selected compounds were further examined in an in vivo hemodynamic model. One compound 1,5-dihydro-4-[4-(1H-imidazol-1- yl)phenyl]-3-methyl-2H-pyrrol-2-one, was identified as a potent and selective positive inotropic agent and inhibitor of cardiac cAMP PDE.
|
Inhibition of PDE 3 (phosphodiesterase III) from guinea pig ventricle
|
Cavia porcellus
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : Cyclic nucleotide phosphodiesterase inhibition by imidazopyridines: analogues of sulmazole and isomazole as inhibitors of the cGMP specific phosphodiesterase.
Year : 1993
Volume : 36
Issue : 10
First Page : 1387
Last Page : 1392
Authors : Coates WJ, Connolly B, Dhanak D, Flynn ST, Worby A.
Abstract : The synthesis and phosphodiesterase (PDE) inhibitory profile of a series of imidazopyridines, including sulmazole and isomazole, on separated PDE isoenzymes are described. The results show that both sulmazole and isomazole are weak inhibitors of PDE III, and their inotropic activity is unlikely to be due to PDE III inhibition alone. Surprisingly, both compounds were found to be significant inhibitors of the cGMP specific isoenzyme, PDE V, and a series of simple 2-substituted phenylimidazo[4,5-b]pyridines have been made to investigate the SAR of PDE activity. This has been shown to be sensitive to chain length, polarity, and the nature of the heteroatom linking group. Potent PDE V inhibitors, many of which are also significant inhibitors of PDE IV, have been identified.
|
Inhibitory activity against cGMP-phosphodiesterase from porcine aorta
|
Sus scrofa
|
740.0
nM
|
|
Journal : J. Med. Chem.
Title : Cyclic GMP phosphodiesterase inhibitors. 2. Requirement of 6-substitution of quinazoline derivatives for potent and selective inhibitory activity.
Year : 1994
Volume : 37
Issue : 13
First Page : 2106
Last Page : 2111
Authors : Takase Y, Saeki T, Watanabe N, Adachi H, Souda S, Saito I.
Abstract : We synthesized various 4-[[3,4-(methylenedioxy)benzyl]amino]quinazolines substituted at the 5- to 8-positions and evaluated their inhibitory activities toward cyclic GMP phosphodiesterase (cGMP-PDE) from porcine aorta. Monosubstitution at the 6-position was essential for the inhibitory activity, and the preferred substituents were compact and hydrophobic: methoxy (3b, IC50 = 0.23 microM), methyl (3c, 0.10 microM), chloro (3d, 0.019 microM), thiomethyl (3f, 0.031 microM), and cyano (3p, 0.090 microM) groups. Compounds 3b-d,f,p lacked inhibitory activity toward other PDE isozymes (all IC50 values > 100 microM), and their relaxing activities in porcine coronary arteries were well correlated with the inhibitory activities toward cGMP-PDE (r = 0.88, p < 0.05). One of these compounds, 3b, elevated the intracellular cGMP level in isolated porcine coronary arteries without causing any change in the cAMP level. We consider that this series of compounds dilates coronary arteries via potent and specific inhibition of cGMP-PDE.
|
In vitro inhibitory activity against cAMP phosphodiesterase III in dog aorta
|
Canis lupus familiaris
|
360.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel cAMP PDE III inhibitors: imidazo[4,5-b]pyridin-2(3H)-ones and thiazolo[4,5-b]pyridin-2(3H)-ones and their analogs.
Year : 1994
Volume : 37
Issue : 2
First Page : 248
Last Page : 254
Authors : Singh B, Bacon ER, Robinson S, Fritz RK, Lesher GY, Kumar V, Dority JA, Reuman M, Kuo GH, Eissenstat MA.
Abstract : The transformation of milrinone to 1,3-dihydro-5-methyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one (13a), 5-methyl-6-(4-pyridinyl)thiazolo[4,5-b]pyridin-2(3H)-one (51), and 7-methyl-6-(4-pyridinyl)-1,8-naphthyridin-2(1H)-one (22) resulted in very potent cAMP PDE III inhibitors with in vitro activity in the nanomolar range. 1,3-Dihydro-2H-imidazo[4,5-b]pyridin-2-ones 13 were prepared from 2-aminopyridine-3-carboxylic acids (7, 10) via Curtius rearrangement. 1,8-Naphthyridin-2(1H)-one 22 and the corresponding 3,4-dihydro derivative 28 were prepared from 5-bromo-2-methyl[3,4'-bipyridin]-6-amine (21) and 5-bromo-2-methyl[3,4-bipyridin]-6(1H)-one (24), respectively, via Heck reaction. Thiazolo[4,5-b]pyridin-2(3H)-ones 35 were prepared from 6-bromo[3,4'-bipyridin]-6-amines 30 and 32 via a four-step sequence. Treatment of 6-amino-2-methyl[3,4'-bipyridine]-5-thiol (59) with ethyl bromoacetate and ethyl bromodifluoroacetate gave pyridothiazinones 60 and 61, respectively.
|
Inhibitory activity against cGMP inhibited Phosphodiesterase 3, isolated from guinea pig ventricular tissue
|
Cavia porcellus
|
730.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological activities of new thieno[3,2-d] pyrimidines as selective type 4 phosphodiesterase inhibitors.
Year : 1998
Volume : 41
Issue : 21
First Page : 4021
Last Page : 4035
Authors : Crespo MI, Pagès L, Vega A, Segarra V, López M, Doménech T, Miralpeix M, Beleta J, Ryder H, Palacios JM.
Abstract : A common pharmacophore for compounds structurally related to nitraquazone has been derived. Using this pharmacophore, new structures have been designed, synthesized, and evaluated for their inhibitory potencies against cyclic adenosine 5'-monophosphate (cAMP) specific phosphodiesterase (PDE 4). From these compounds, 4-benzylamino-2-butylthieno[3,2-d]pyrimidine (4) was selected for optimization. The effects of changes to the lipophilic groups and the amino linkage on the PDE 4 activity have been investigated. As a result, some potent PDE 4 inhibitors, selective with respect to PDE 3, have been identified. A selected group of compounds have been further evaluated for their ability to displace [3H]rolipram from its binding site and also to potentiate isoprenaline-induced cAMP accumulation in isolated guinea pig eosinophils. Of these, 2-butyl-4-cyclohexylaminothieno[3,2-d]pyrimidine (33) has an interesting profile, with an important improvement in PDE 4/[3H]rolipram ratio with respect to reference drugs, and good activity in cAMP potentiation, consistent with efficient cell penetration.
|
Inhibition of guinea pig ventricular Phosphodiesterase 3
|
Cavia porcellus
|
730.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel heterocyclic-fused pyridazinones as potent and selective phosphodiesterase IV inhibitors.
Year : 1997
Volume : 40
Issue : 10
First Page : 1417
Last Page : 1421
Authors : Dal Piaz V, Giovannoni MP, Castellana C, Palacios JM, Beleta J, Doménech T, Segarra V.
Abstract : A series of 6-aryl-4,5-heterocyclic-fused pyridazinones were designed and synthesized as selective phosphodiesterase (PDE) IV inhibitors. Biological evaluation of these compounds demonstrated a good selectivity profile toward the PDE IV family and greatly attenuated affinity for the Rolipram high-affinity binding site that seems to be responsible for undesiderable side effects. Structure-activity relationships (SARs) studies showed that the presence of an ethyl group at pyridazine N-2 is associated with the best potency and selectivity profile.
|
Inhibition of human platelet phosphodiesterase 3
|
Homo sapiens
|
600.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : PDE2 inhibition by the PI3 kinase inhibitor LY294002 and analogues.
Year : 2004
Volume : 14
Issue : 11
First Page : 2847
Last Page : 2851
Authors : Abbott BM, Thompson PE.
Abstract : Synthetic 2-morpholinochromones, including the known PI3-kinase inhibitor LY294002, have been evaluated in vitro as inhibitors of isolated human platelet phosphodiesterases. Inhibition of the cAMP-phosphodiesterases, PDE2 and PDE3 by LY294002 is reported for the first time. Preliminary screening across a range of 2-morpholinochromones has revealed structural features for optimised PDE2 inhibition.
|
Inhibition of phosphodiesterase 3 (PDE3) from porcine platelets, range 0.581-1.23
|
Sus scrofa
|
843.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-(3-Chloro-4-methoxybenzyl)aminophthalazines: synthesis and inhibitory activity toward phosphodiesterase 5.
Year : 2000
Volume : 43
Issue : 13
First Page : 2523
Last Page : 2529
Authors : Watanabe N, Adachi H, Takase Y, Ozaki H, Matsukura M, Miyazaki K, Ishibashi K, Ishihara H, Kodama K, Nishino M, Kakiki M, Kabasawa Y.
Abstract : We synthesized various 4-(3-chloro-4-methoxybenzyl)aminophthalazines substituted at the 1- and 6-positions and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) and their vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F2alpha (10(-5) M). The preferred substituents at the 1-position of the phthalazine were 4-hydroxypiperidino, 4-hydroxymethylpiperidino, 4-(2-hydroxyethyl)piperidino, and 4-oxopiperidino. Among these compounds, [4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxy)piperidino]-6-phthala zinecarbonitrile monohydrochloride (13) exhibited potent PDE5 inhibitory activity (IC(50) = 0.56 nM) with >1700-fold high selectivity over other PDE isozymes (PDE1-4). Compound 13 exhibited the most potent vasorelaxant action (EC(50) = 13 nM) in this series of compounds. Compound 13 reduced mean pulmonary arterial pressure by 29.9 +/- 3.1% when administered intravenously at 30 microg/kg to the chronically hypoxic rats and had an apparent oral bioavailability of about 19.5% in rats and was selected for further biological evaluation.
|
Inhibition of Phosphodiesterase 3
|
Rattus norvegicus
|
930.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Imidazotriazinone inhibitors of the Ca2+-calmodulin sensitive phosphodiesterase (PDE I)
Year : 1997
Volume : 7
Issue : 1
First Page : 89
Last Page : 94
Authors : Hlasta DJ, Bode DC, Court JJ, Desai RC, Pagani ED, Silver PJ
|
Inhibition of Phosphodiesterase 3 from rat diaphragm
|
Rattus norvegicus
|
740.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A prenylated flavonol, sophoflavescenol: a potent and selective inhibitor of cGMP phosphodiesterase 5.
Year : 2002
Volume : 12
Issue : 17
First Page : 2313
Last Page : 2316
Authors : Shin HJ, Kim HJ, Kwak JH, Chun HO, Kim JH, Park H, Kim DH, Lee YS.
Abstract : During the search for naturally occurring cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) inhibitors, it was found that the extracts from Sophora flavescens exhibit potent inhibitory activity against cGMP PDE5 prepared from rat diaphragm. Therefore, the inhibitory activities of five flavonoids, kushenol H (1), kushenol K (2), kurarinol (3), sophoflavescenol (4) and kuraridine (5), isolated from S. flavescens were measured against cGMP PDE5 to identify potent cGMP PDE5 inhibitory constituents. Among tested compounds, sophoflavescenol (4), a C-8 prenylated flavonol, showed the most potent inhibitory activity (IC(50)=0.013 microM) against cGMP PDE5 with 31.5- and 196.2-fold selectivity over PDE3 and PDE4, respectively. Kinetic analysis revealed that sophoflavescenol was a mixed inhibitor of PDE5 with a K(i) value of 0.005 microM.
|
Inhibitory concentration required to inhibit human phosphodiesterase 3A expressed in Escherichia coli
|
None
|
440.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Benzyl vinylogous amide substituted aryldihydropyridazinones and aryldimethylpyrazolones as potent and selective PDE3B inhibitors.
Year : 2003
Volume : 13
Issue : 22
First Page : 3983
Last Page : 3987
Authors : Edmondson SD, Mastracchio A, He J, Chung CC, Forrest MJ, Hofsess S, MacIntyre E, Metzger J, O'Connor N, Patel K, Tong X, Tota MR, Van der Ploeg LH, Varnerin JP, Fisher MH, Wyvratt MJ, Weber AE, Parmee ER.
Abstract : Aryldihydropyridazinones and aryldimethylpyrazolones with 2-benzyl vinylogous amide substituents have been identified as potent PDE3B subtype selective inhibitors. Dihydropyridazinone 8a (PDE3B IC(50)=0.19 nM, 3A IC(50)=1.3 nM) was selected for in vivo evaluation of lipolysis induction, metabolic rate increase, and cardiovascular effects.
|
Inhibitory concentration required to inhibit human phosphodiesterase 3B expressed in Escherichia coli
|
None
|
280.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Benzyl vinylogous amide substituted aryldihydropyridazinones and aryldimethylpyrazolones as potent and selective PDE3B inhibitors.
Year : 2003
Volume : 13
Issue : 22
First Page : 3983
Last Page : 3987
Authors : Edmondson SD, Mastracchio A, He J, Chung CC, Forrest MJ, Hofsess S, MacIntyre E, Metzger J, O'Connor N, Patel K, Tong X, Tota MR, Van der Ploeg LH, Varnerin JP, Fisher MH, Wyvratt MJ, Weber AE, Parmee ER.
Abstract : Aryldihydropyridazinones and aryldimethylpyrazolones with 2-benzyl vinylogous amide substituents have been identified as potent PDE3B subtype selective inhibitors. Dihydropyridazinone 8a (PDE3B IC(50)=0.19 nM, 3A IC(50)=1.3 nM) was selected for in vivo evaluation of lipolysis induction, metabolic rate increase, and cardiovascular effects.
|
In vitro vascular relaxation in canine mesenteric veins precontracted with phenylephrine.
|
Canis lupus familiaris
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel compounds possessing potent cAMP and cGMP phosphodiesterase inhibitory activity. Synthesis and cardiovascular effects of a series of imidazo[1,2-a]quinoxalinones and imidazo[1,5-a]quinoxalinones and their aza analogues.
Year : 1991
Volume : 34
Issue : 9
First Page : 2671
Last Page : 2677
Authors : Davey DD, Erhardt PW, Cantor EH, Greenberg SS, Ingebretsen WR, Wiggins J.
Abstract : A series of novel imidazoquinoxalinones and their aza analogues were prepared by the cyclization of o-amino(1H-imidazol-1-yl)aryls and heteroaryls with carbonyldiimidazole. The compounds were screened for inhibition of Type I and Type IV phosphodiesterases (PDE's) and evaluated for their vasorelaxant and positive inotropic activities in vitro. In general, compounds having potent PDE inhibitory activity also possessed good inotropic and vasodilator activity, although linear correlations between these activities could not be established.
|
Inhibition of cAMP Phosphodiesterase 3
|
Canis lupus familiaris
|
360.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel cAMP PDE III inhibitors: 1,6-naphthyridin-2(1H)-ones.
Year : 1992
Volume : 35
Issue : 26
First Page : 4858
Last Page : 4865
Authors : Singh B, Lesher GY, Pluncket KC, Pagani ED, Bode DC, Bentley RG, Connell MJ, Hamel LT, Silver PJ.
Abstract : Two series of medorinone (3) analogs were prepared by modifications at C(2) and C(5). The C(2)-series was prepared from 2-chloro-5-methyl-1,6-naphthyridine (4) by replacement of the chloro group with various nucleophiles. The C(5)-series was prepared from 5-acyl-6-[2-(dimethylamino)-ethenyl]-2(1H)-pyridinone (11), 5-bromo-1,6-naphthyridin-2(1H)-one (17), and 1,3-diketones 19 and 27. 1,6-Naphthyridin-2(1H)-ones are novel inhibitors of cAMP PDE III. Modification of the carbonyl group of 3 or N-methylation at N(1) resulted in a dramatic loss of enzyme activity. Absence of the C(5)-methyl group of medorinone (3) or its shift to C(3) or C(7) also resulted in reduced activity. Substitution at C(3) also diminished activity. However, substitution at C(5) by a wide variety of substituents led to improvement of enzyme activity and several C(5)-substituted analogs were more potent than milrinone.
|
In vivo inhibition of cyclic AMP phosphodiesterase from human platelets
|
Homo sapiens
|
860.0
nM
|
|
Journal : J. Med. Chem.
Title : Inhibitors of cyclic AMP phosphodiesterase. 2. Structural variations of N-cyclohexyl-N-methyl-4-[(1,2,3,5-tetrahydro- 2-oxoimidazo[2,1-b]quinazolin-7-yl)-oxy]butyramide (RS-82856).
Year : 1987
Volume : 30
Issue : 2
First Page : 303
Last Page : 318
Authors : Venuti MC, Jones GH, Alvarez R, Bruno JJ.
Abstract : A series of analogues of the cyclic AMP phosphodiesterase (PDE) inhibitor N-cyclohexyl-N-methyl-4-[(1,2,3,5-tetrahydro- 2-oxoimidazo[2,1-b]quinazolin-7-yl)oxy]butyramide (RS-82856, 1) was prepared by systematic variation of the side-chain substituent, length, position, connecting atom, and the parent heterocycle itself. The compounds were evaluated as inhibitors of cyclic AMP phosphodiesterase from both human platelets and rat or dog heart tissue and as inhibitors of ADP-induced platelet aggregation. Structure-activity correlations for the analogue series revealed significant limitations on the steric bulk of substituents on the 1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one heterocycle and the position and length of the side chain. As inhibitors of cyclic AMP phosphodiesterase (PDE), potency steadily increased with increasingly lipophilic side chains. In platelet aggregation inhibition studies, however, a maximum in activity was reached with 1, while more lipophilic compounds were significantly less active. Major changes in the heterocycle itself, represented by isomeric and other carbonyl variations, also decreased activity. The molecular features defined by this series of analogues of 1 correlate to a high degree with current understanding of the chemical and topographical requirements of the active site of the FIII (type IV) form of cyclic AMP PDE. Selective inhibition of this enzyme has been proposed as the principal component of the positive inotropic action of a number of cardiotonic agents.
|
Inhibition of platelet cAMP phosphodiesterase
|
Homo sapiens
|
860.0
nM
|
|
Journal : J. Med. Chem.
Title : Inhibitors of cyclic AMP phosphodiesterase. 3. Synthesis and biological evaluation of pyrido and imidazolyl analogues of 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline.
Year : 1988
Volume : 31
Issue : 11
First Page : 2136
Last Page : 2145
Authors : Venuti MC, Stephenson RA, Alvarez R, Bruno JJ, Strosberg AM.
Abstract : Hybridization of structural elements of 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline ring system common to the cyclic AMP (cAMP) phosphodiesterase (PDE) inhibitors lixazinone (RS-82856, 1) and anagrelide (3) with complementary features of other PDE inhibitor cardiotonic agents prompted the design and synthesis of the title compounds 7a-d, 11, 12, and 13a,b. The necessary features of these compounds were determined within the framework of the proposed active-site models for the high affinity form of cAMP PDE inhibited by cGMP (type IV). Evaluation of these targets, both in vitro as inhibitors of platelet or cardiac type IV PDE or in vivo as inotropic agents in the pentobarbital-anesthetized dog model of congestive heart failure, showed that these structure possessed negligibly enhanced activities over the parent heterocyclic system, and remained significantly inferior to 1 in all respects. This difference is ascribed to the absence of the N-cyclohexyl-N-methylbutyramidyl-4-oxy side chain of 1. The proposal that the acidic lactam-type functionality, common to the type IV PDE inhibitor inotropic agents such as 4-6 and 8-10, mimics the polarizable cyclic phosphate moiety of cAMP suggested that the side chain of 1 may function as an effective surrogate for selected characteristics of the adenine portion of cAMP. However, the results of this study show that incorporation of adenine-like hydrogen-bonding functionalities common to other type IV PDE inhibitors into the 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline system did not enhance activity to the levels observed for 1 and analogues. These observations, coupled with the kinetic pattern of inhibition of type IV PDE observed for 1 and analogues, suggest that access to a secondary, lipophilic-tolerant binding site, possibly coincident with the adenine binding domain, and adjacent to the catalytic ribose-phosphate binding site of platelet and cardiac type IV PDE, is responsible for the increased potency of these compounds.
|
Inhibition of human phosphodiesterase 3
|
Homo sapiens
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : The next generation of phosphodiesterase inhibitors: structural clues to ligand and substrate selectivity of phosphodiesterases.
Year : 2005
Volume : 48
Issue : 10
First Page : 3449
Last Page : 3462
Authors : Manallack DT, Hughes RA, Thompson PE.
|
Inhibition of human platelet PDE3
|
Homo sapiens
|
210.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro antiplatelet activity of new 4-(1-piperazinyl)coumarin derivatives. Human platelet phosphodiesterase 3 inhibitory properties of the two most effective compounds described and molecular modeling study on their interactions with phosphodiesterase 3A catalytic site.
Year : 2007
Volume : 50
Issue : 12
First Page : 2886
Last Page : 2895
Authors : Roma G, Di Braccio M, Grossi G, Piras D, Leoncini G, Bruzzese D, Signorello MG, Fossa P, Mosti L.
Abstract : The synthesis and in vitro antiplatelet activity significant data of coumarin derivatives 5i-x and quinolin-2(1H)-one derivatives 22a,b, as well as the corresponding structure-activity relationships are described. The recently reported 8-methyl-4-(1-piperazinyl)-7-(3-pyridylmethoxy)coumarin 5f and its potent 7-(2-morpholinoethoxy)-substituted new analogue 5u were notably more effective inhibitors of pure human platelet PDE3 than milrinone and cilostazol: these data were related, through a molecular modeling study, with the molecular interactions of the four compounds with the human PDE3A catalytic site.
|
Vasorelaxant effect in rabbit pulmonary artery assessed as inhibition of KCl-induced contraction at 100 uM
|
Oryctolagus cuniculus
|
60.5
%
|
|
Journal : Bioorg. Med. Chem.
Title : Pyridazinone derivatives: design, synthesis, and in vitro vasorelaxant activity.
Year : 2008
Volume : 16
Issue : 1
First Page : 382
Last Page : 389
Authors : Abouzid K, Abdel Hakeem M, Khalil O, Maklad Y.
Abstract : In an attempt to identify potential vasodilator-cardiotonic lead compounds, three series of pyridazinones were designed using three-dimensional pharmacophore developed with CATALYST software from a set of potent cyclic nucleotide phosphodiesterase III, cAMP PDEIII inhibitors. The features of the target compounds were based on the structures of many biologically active lead compounds with cAMP phosphodiesterase III inhibiting activity such as Milrinone and others. Compounds with higher fit scores to the developed pharmacophore were synthesized namely; 6-(3-ethoxycarbonyl-4-oxo-1,4-dihydroquinolin-6-yl)-4,5-dihydro-3(2H)-pyridazinones (3a and 3b), 6-[4-(2,6-disubstituted-quinolin-4-ylamino)phenyl]-4,5-dihydropyridazin-3(2H)-ones (5a-f), and 6-[3-(5-cyano-6-oxo-4-aryl-1,6-dihydro-2-pyridyl)phenylamino]-3(2H)pyridazinone (8a and 8b). The vasodilator activity of the newly synthesized compounds was examined on the isolated main pulmonary artery of the rabbit. Some of the tested compounds showed moderate vasorelaxant activity compared with standard drug, Milrinone.
|
Inhibition of human phosphodiesterase 3
|
Homo sapiens
|
270.0
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 human recombinant PDE3A assessed as cGMP hydrolysis at 50 uM after 60 mins by fluorescence polarization assay using tetramethylrhodamine-tagged cGMP as substrate
|
Homo sapiens
|
95.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of novel pyridine derivatives as anticancer agents and phosphodiesterase 3 inhibitors.
Year : 2009
Volume : 17
Issue : 16
First Page : 5974
Last Page : 5982
Authors : Abadi AH, Ibrahim TM, Abouzid KM, Lehmann J, Tinsley HN, Gary BD, Piazza GA.
Abstract : Two series of 4,6-diaryl-2-imino-1,2-dihydropyridine-3-carbonitriles and their isosteric 4,6-diaryl-2-oxo-1,2-dihydropyridine-3-carbonitriles were synthesized through a combinatorial approach. The prepared analogues were evaluated for their in vitro capacity to inhibit PDE3A and the growth of the human HT-29 colon adenocarcinoma tumor cell line. Compound 6-(4-bromophenyl)-4-(2-ethoxyphenyl)-2-imino-1,2-dihydropyridine-3-carbonitrile (Id) exhibited the strongest PDE3 inhibition when cGMP but not cAMP is the substrate with a IC(50)of 27microM, which indicates a highly selective mechanism of enzyme inhibition. On the other hand, compound 6-(1,3-benzodioxol-5-yl)-4-(2-ethoxyphenyl)-2-imino-1,2-dihydropyridine-3-carbonitrile (Ii) was the most active in inhibiting colon tumor cell growth with a IC(50) of 3microM. The electronic effects, steric effects and conformational aspects of Id seem to be the most crucial for the PDE3 inhibition. Meanwhile, steric factors and the H-bonding capability seem to be the most important factors for tumor cell growth inhibitory activity. Conversely, there is no direct correlation between PDE3 inhibition and anticancer activity for the prepared compounds. An in silico docking experiment indicates the potential involvement of other potential molecular targets such as PIM-1 kinase to explain its tumor cell growth inhibitory activity.
|
Inhibition of human recombinant PDE3A assessed as cAMP hydrolysis at 50 uM after 60 mins by fluorescence polarization assay using fluorescein-tagged cAMP as substrate
|
Homo sapiens
|
77.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of novel pyridine derivatives as anticancer agents and phosphodiesterase 3 inhibitors.
Year : 2009
Volume : 17
Issue : 16
First Page : 5974
Last Page : 5982
Authors : Abadi AH, Ibrahim TM, Abouzid KM, Lehmann J, Tinsley HN, Gary BD, Piazza GA.
Abstract : Two series of 4,6-diaryl-2-imino-1,2-dihydropyridine-3-carbonitriles and their isosteric 4,6-diaryl-2-oxo-1,2-dihydropyridine-3-carbonitriles were synthesized through a combinatorial approach. The prepared analogues were evaluated for their in vitro capacity to inhibit PDE3A and the growth of the human HT-29 colon adenocarcinoma tumor cell line. Compound 6-(4-bromophenyl)-4-(2-ethoxyphenyl)-2-imino-1,2-dihydropyridine-3-carbonitrile (Id) exhibited the strongest PDE3 inhibition when cGMP but not cAMP is the substrate with a IC(50)of 27microM, which indicates a highly selective mechanism of enzyme inhibition. On the other hand, compound 6-(1,3-benzodioxol-5-yl)-4-(2-ethoxyphenyl)-2-imino-1,2-dihydropyridine-3-carbonitrile (Ii) was the most active in inhibiting colon tumor cell growth with a IC(50) of 3microM. The electronic effects, steric effects and conformational aspects of Id seem to be the most crucial for the PDE3 inhibition. Meanwhile, steric factors and the H-bonding capability seem to be the most important factors for tumor cell growth inhibitory activity. Conversely, there is no direct correlation between PDE3 inhibition and anticancer activity for the prepared compounds. An in silico docking experiment indicates the potential involvement of other potential molecular targets such as PIM-1 kinase to explain its tumor cell growth inhibitory activity.
|
Vasorelaxant activity against noradrenaline-induced contraction in intact rat aortic rings
|
Rattus norvegicus
|
122.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New pyridazinone derivatives with vasorelaxant and platelet antiaggregatory activities.
Year : 2010
Volume : 20
Issue : 22
First Page : 6624
Last Page : 6627
Authors : Costas T, Besada P, Piras A, Acevedo L, Yañez M, Orallo F, Laguna R, Terán C.
Abstract : New 6-substituted and 2,6-disubstituted pyridazinone derivatives were obtained starting from easily accessible alkyl furans by using oxidation with singlet oxygen to give 4-methoxy or 4-hydroxybutenolides, key intermediates of this synthetic strategy. The new pyridazinone derivatives have been studied as vasorelaxant and antiplatelet agents. Analysis of biological data revealed the silyl ethers (4a-i) and N,O-dibenzyl derivatives (6g-i) as the most active compounds.
|
PUBCHEM_BIOASSAY: Luminescence Cell-Based Dose Confirmation HTS to Identify Inhibitors of Platelet Dense Granule Release. (Class of assay: confirmatory) [Related pubchem assays: 1663 (Primary HTS), 1678 (Summary of Project)]
|
None
|
634.0
nM
|
|
Title : PubChem BioAssay data set
|
DRUGMATRIX: Phosphodiesterase PDE3 enzyme inhibition (substrate: [3H]cAMP + cAMP)
|
Homo sapiens
|
958.5
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 PDE3 at 500 uM by Biomol Green quantizyme assay system
|
Homo sapiens
|
90.61
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of novel 2-pyridone derivatives as inhibitors of phosphodiesterase3 (PDE3): a target for heart failure and platelet aggregation.
Year : 2012
Volume : 22
Issue : 18
First Page : 6010
Last Page : 6015
Authors : Ravinder M, Mahendar B, Mattapally S, Hamsini KV, Reddy TN, Rohit C, Srinivas K, Banerjee SK, Rao VJ.
Abstract : Twenty-six 2-pyridone derivatives (8a-8z), which are structurally analogous to amrinone and milrinone two important cardiotonic drugs, are synthesized and characterized. The synthesis of 2-pyridone derivatives involves addition, followed by cyclization between Baylis-Hillman acetates (7a-7k) and enamino esters or nitriles (3a-3e). Thus synthesized pyridones were subjected to PDE3 inhibitory activity, 14 pyridones were found to be hits out of 26 pyridones synthesized and out of 14 hits, there are 5 pyridones found to be lead compounds having excellent PDE3 inhibitory activity. Further we have carried out computational analysis to understand protein/enzyme and 2-pyridone derivative interactions to identify amino acid residues involved in the vicinity of binding and compared with milrinone drug.
|
Inhibition of PDE3 at 10 uM by Biomol Green quantizyme assay system
|
Homo sapiens
|
91.67
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of novel 2-pyridone derivatives as inhibitors of phosphodiesterase3 (PDE3): a target for heart failure and platelet aggregation.
Year : 2012
Volume : 22
Issue : 18
First Page : 6010
Last Page : 6015
Authors : Ravinder M, Mahendar B, Mattapally S, Hamsini KV, Reddy TN, Rohit C, Srinivas K, Banerjee SK, Rao VJ.
Abstract : Twenty-six 2-pyridone derivatives (8a-8z), which are structurally analogous to amrinone and milrinone two important cardiotonic drugs, are synthesized and characterized. The synthesis of 2-pyridone derivatives involves addition, followed by cyclization between Baylis-Hillman acetates (7a-7k) and enamino esters or nitriles (3a-3e). Thus synthesized pyridones were subjected to PDE3 inhibitory activity, 14 pyridones were found to be hits out of 26 pyridones synthesized and out of 14 hits, there are 5 pyridones found to be lead compounds having excellent PDE3 inhibitory activity. Further we have carried out computational analysis to understand protein/enzyme and 2-pyridone derivative interactions to identify amino acid residues involved in the vicinity of binding and compared with milrinone drug.
|
Inhibition of PDE3 at 1 nmol by Biomol Green quantizyme assay system
|
Homo sapiens
|
29.27
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of novel 2-pyridone derivatives as inhibitors of phosphodiesterase3 (PDE3): a target for heart failure and platelet aggregation.
Year : 2012
Volume : 22
Issue : 18
First Page : 6010
Last Page : 6015
Authors : Ravinder M, Mahendar B, Mattapally S, Hamsini KV, Reddy TN, Rohit C, Srinivas K, Banerjee SK, Rao VJ.
Abstract : Twenty-six 2-pyridone derivatives (8a-8z), which are structurally analogous to amrinone and milrinone two important cardiotonic drugs, are synthesized and characterized. The synthesis of 2-pyridone derivatives involves addition, followed by cyclization between Baylis-Hillman acetates (7a-7k) and enamino esters or nitriles (3a-3e). Thus synthesized pyridones were subjected to PDE3 inhibitory activity, 14 pyridones were found to be hits out of 26 pyridones synthesized and out of 14 hits, there are 5 pyridones found to be lead compounds having excellent PDE3 inhibitory activity. Further we have carried out computational analysis to understand protein/enzyme and 2-pyridone derivative interactions to identify amino acid residues involved in the vicinity of binding and compared with milrinone drug.
|
Inhibition of Cavia porcellus (guinea pig) PDE3 isolated from heart using [3H]cAMP as substrate at 100 uM by two-step method
|
Cavia porcellus
|
93.0
%
|
|
Journal : Med Chem Res
Title : Quinolinedione nucleus as a novel scaffold for A1 and A2A adenosine receptor antagonists
Year : 2008
Volume : 17
Issue : 9
First Page : 587
Last Page : 603
Authors : Mosti L, Fossa P, Menozzi G, Trincavelli L, Floreani M
|
Inhibition of Cavia porcellus (guinea pig) PDE3 isolated from heart using [3H]cAMP as substrate at 50 uM by two-step method
|
Cavia porcellus
|
90.27
%
|
|
Journal : Med Chem Res
Title : Quinolinedione nucleus as a novel scaffold for A1 and A2A adenosine receptor antagonists
Year : 2008
Volume : 17
Issue : 9
First Page : 587
Last Page : 603
Authors : Mosti L, Fossa P, Menozzi G, Trincavelli L, Floreani M
|
Inhibition of Cavia porcellus (guinea pig) PDE3 isolated from heart using [3H]cAMP as substrate at 10 uM by two-step method
|
Cavia porcellus
|
58.7
%
|
|
Journal : Med Chem Res
Title : Quinolinedione nucleus as a novel scaffold for A1 and A2A adenosine receptor antagonists
Year : 2008
Volume : 17
Issue : 9
First Page : 587
Last Page : 603
Authors : Mosti L, Fossa P, Menozzi G, Trincavelli L, Floreani M
|
Inhibition of Cavia porcellus (guinea pig) PDE3 isolated from heart using [3H]cAMP as substrate at 1 uM by two-step method
|
Cavia porcellus
|
22.22
%
|
|
Journal : Med Chem Res
Title : Quinolinedione nucleus as a novel scaffold for A1 and A2A adenosine receptor antagonists
Year : 2008
Volume : 17
Issue : 9
First Page : 587
Last Page : 603
Authors : Mosti L, Fossa P, Menozzi G, Trincavelli L, Floreani M
|
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
|
14.68
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-0.64
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
13.45
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
42.18
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
26.3
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
3.54
%
|
|
|
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
|
-6.55
%
|
|
|
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
|
5.85
%
|
|
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.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
6.52
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
8.094
%
|
|
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
|
-0.12
%
|
|
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
|
-0.2
%
|
|
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
|
-0.12
%
|
|
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
|
-0.2
%
|
|
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.
|
Inhibition of human recombinant PDE3A using cAMP as substrate incubated for 20 mins measured by Kinase Glo reagent based microplate reader assay
|
Homo sapiens
|
250.0
nM
|
|
Journal : Eur J Med Chem
Title : New imidazopyridines with phosphodiesterase 4 and 7 inhibitory activity and their efficacy in animal models of inflammatory and autoimmune diseases.
Year : 2021
Volume : 209
First Page : 112854
Last Page : 112854
Authors : Ručilová V,Świerczek A,Vanda D,Funk P,Lemrová B,Gawalska A,Bucki A,Nowak B,Zadrożna M,Pociecha K,Soural M,Wyska E,Pawłowski M,Chłoń-Rzepa G,Zajdel P
Abstract : Herein, we describe the rapid synthesis of a focused library of trisubstituted imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines from 2,4-dichloro-3-nitropyridine using the combination of solution-phase/solid-phase chemistry as new potential anti-inflammatory agents in the treatment of autoimmune diseases. Structure-activity relationship studies, followed by the structure optimization, provided hit compounds (17 and 28) which inhibited phosphodiesterase 4 (PDE4) with IC values comparable to rolipram and displayed different inhibitory potency against phosphodiesterase 7 (PDE7). Among them, compound 17 showed a beneficial effect in all the studied animal models of inflammatory and autoimmune diseases (concanavalin A-induced hepatitis, lipopolysaccharide-induced endotoxemia, collagen-induced arthritis, and MOG-induced encephalomyelitis). In addition, compound 17 showed a favorable pharmacokinetic profile after intraperitoneal administration; it was characterized by a fast absorption from the peritoneal cavity and a relatively long terminal half-life in rats. It was found to penetrate brain barrier in mice. The performed experiments sheds light on the impact of PDE7A inhibition for the efficacy of PDE4 inhibitors in these disease conditions.
