|
Binding affinity for Angiotensin II receptor, type 1 measured by ability to displace [125I]- A II from its specific binding site in rat liver membrane
|
None
|
1.3
nM
|
|
Journal : J. Med. Chem.
Title : A new series of imidazolones: highly specific and potent nonpeptide AT1 angiotensin II receptor antagonists.
Year : 1993
Volume : 36
Issue : 22
First Page : 3371
Last Page : 3380
Authors : Bernhart CA, Perreaut PM, Ferrari BP, Muneaux YA, Assens JL, Clément J, Haudricourt F, Muneaux CF, Taillades JE, Vignal MA.
Abstract : Starting from the structure of the novel nonpeptide AT1 receptor antagonist DuP 753 (losartan), a new series of potent antagonists was designed. In these compounds the central imidazole nucleus was replaced by the dihydroimidazol-4-one structure. The most active compounds had a spirocyclopentane or a spirocyclohexane ring in position 5. Like the imidazole series, the best substituents were the linear butyl chain in position 1 and the [2'-(tetrazol-5-yl)biphenylyl]methyl group in position 3. Antagonistic activity was assessed by the ability of the compounds to competitively inhibit [125I]AII binding to the AT1 subtype receptor and to antagonize AII-induced contractions in rabbit aorta rings. The most active compounds had IC50 values in the nanomolar range. In conscious rats, compounds 4 and 21 antagonized the AII pressor response when administered orally. Compound 21 (SR 47436) was the most active; it was recently shown to also be active in cynomolgus monkeys both intravenously and orally. This molecule is now undergoing clinical trials for the treatment of hypertension.
|
Binding affinity towards Angiotensin II receptor, type 1 in rat liver membrane using [125I]-angiotensin II (0.1 nM)
|
Rattus norvegicus
|
1.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Development of tetrazole bioisosteres in angiotensin II antagonists
Year : 1994
Volume : 4
Issue : 1
First Page : 45
Last Page : 50
Authors : Ferrari B, Taillades J, Perreaut P, Bernhart C, Gougat J, Guiraudou P, Cazaubon C, Roccon A, Nisato D, Le Fur G, Breliere J
|
In vitro inhibition of specific binding of [125I]AII to Angiotensin II receptor, type 1 from rat liver membrane
|
None
|
1.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cyclopentanespiro-3H-dihydro-pyrimidinones as Angiotensin II AT1 receptor antagonists
Year : 1994
Volume : 4
Issue : 1
First Page : 157
Last Page : 162
Authors : Bernhart C, Hundricourt F, Assens J, Gougat J, Lacour C, Roccon A, Cazaubon C, Breliere J, Le Fur G, Nisato D
|
Compound was evaluated for its binding affinity towards rat Angiotensin II receptor, type 1
|
None
|
0.8
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-isoxazolyl biphenylsulfonamides as potent dual angiotensin II and endothelin A receptor antagonists.
Year : 2002
Volume : 45
Issue : 18
First Page : 3829
Last Page : 3835
Authors : Murugesan N, Tellew JE, Gu Z, Kunst BL, Fadnis L, Cornelius LA, Baska RA, Yang Y, Beyer SM, Monshizadegan H, Dickinson KE, Panchal B, Valentine MT, Chong S, Morrison RA, Carlson KE, Powell JR, Moreland S, Barrish JC, Kowala MC, Macor JE.
Abstract : The ET(A) receptor antagonist (2) (N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-[1,1'-biphenyl]-2-sulfonamide, BMS-193884) shares the same biphenyl core as a large number of AT(1) receptor antagonists, including irbesartan (3). Thus, it was hypothesized that merging the structural elements of 2 with those of the biphenyl AT(1) antagonists (e.g., irbesartan) would yield a compound with dual activity for both receptors. This strategy led to the design, synthesis, and discovery of (15) (4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-[1,1'-biphenyl]-2-sulfonamide, BMS-248360) as a potent and orally active dual antagonist of both AT(1) and ET(A) receptors. Compound 15 represents a new approach to treating hypertension.
|
Inhibitory activity against Angiotensin II receptor, type 1 in rat liver membrane
|
None
|
1.3
nM
|
|
Journal : J. Med. Chem.
Title : Nonpeptide angiotensin II receptor antagonists: the next generation in antihypertensive therapy.
Year : 1996
Volume : 39
Issue : 3
First Page : 625
Last Page : 656
Authors : Wexler RR, Greenlee WJ, Irvin JD, Goldberg MR, Prendergast K, Smith RD, Timmermans PB.
|
Displacement of [125I]- Ang II from type 1 Angiotensin II receptor
|
Rattus norvegicus
|
0.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Imidazolinones as nonpeptide angiotensin II receptor antagonists
Year : 1994
Volume : 4
Issue : 12
First Page : 1527
Last Page : 1530
Authors : Quan ML, DeLucca I, Boswell GA, Chiu AT, Wong PC, Wexler RR, Timmermans PB
|
Inhibition of [125I]-AII binding to Angiotensin II receptor of rat uterine membrane
|
Rattus norvegicus
|
1.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N1-sterically hindered 2H-imidazol-2-one angiotensin II receptor antagonists: The conversion of surmountable antagonists to insurmountable antagonists
Year : 1993
Volume : 3
Issue : 6
First Page : 1055
Last Page : 1060
Authors : Reitz DB, Garland DJ, Norton MB, Collins JT, Reinhard EJ, Manning RE, Olins GM, Chen ST, Palomo MA, McMahon EG, Koehler KF
|
Binding affinity against AT1 in human hepatoma cell line, PLC-PRF-5
|
None
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological evaluation of new pyrazolidine-3, 5-diones as AT(1) angiotensin II receptor antagonists.
Year : 2000
Volume : 43
Issue : 14
First Page : 2685
Last Page : 2697
Authors : Le Bourdonnec B, Meulon E, Yous S, Goossens JF, Houssin R, Hénichart JP.
Abstract : On the basis of the structure of the non-peptide receptor antagonist irbesartan, a new series of AT(1) ligands was designed. In these compounds the central imidazolone nucleus of irbesartan was replaced by a pyrazolidine-3,5-dione structure. The key intermediate N-alkylpyrazolidine-3,5-diones were synthesized according to a new and general method. The most active compounds possess a spirocyclopentane ring at position 4, a linear butyl chain at position 1, and the [2'-(5-tetrazolyl)biphenyl-4-yl]methyl or [2'-(benzoylaminosulfonyl)biphenyl-4-yl]methyl group at position 2. Affinity toward the AT(1) and AT(2) receptors was assessed by the ability of the compounds to competitively displace [(3)H]AII from its specific binding sites. The most active compounds, 28 and 48, displayed high affinity for the AT(1) receptor, good selectivity AT(1) versus AT(2), and potent in vitro antagonist activity.
|
Compound was evaluated for its binding affinity towards human Angiotensin II receptor, type 1
|
None
|
1.1
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-isoxazolyl biphenylsulfonamides as potent dual angiotensin II and endothelin A receptor antagonists.
Year : 2002
Volume : 45
Issue : 18
First Page : 3829
Last Page : 3835
Authors : Murugesan N, Tellew JE, Gu Z, Kunst BL, Fadnis L, Cornelius LA, Baska RA, Yang Y, Beyer SM, Monshizadegan H, Dickinson KE, Panchal B, Valentine MT, Chong S, Morrison RA, Carlson KE, Powell JR, Moreland S, Barrish JC, Kowala MC, Macor JE.
Abstract : The ET(A) receptor antagonist (2) (N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-[1,1'-biphenyl]-2-sulfonamide, BMS-193884) shares the same biphenyl core as a large number of AT(1) receptor antagonists, including irbesartan (3). Thus, it was hypothesized that merging the structural elements of 2 with those of the biphenyl AT(1) antagonists (e.g., irbesartan) would yield a compound with dual activity for both receptors. This strategy led to the design, synthesis, and discovery of (15) (4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-[1,1'-biphenyl]-2-sulfonamide, BMS-248360) as a potent and orally active dual antagonist of both AT(1) and ET(A) receptors. Compound 15 represents a new approach to treating hypertension.
|
In vitro binding affinity towards Angiotensin II receptor, type 1 of human hepatoma cell line PLC-PRF-5
|
None
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Comparison of 3D structures and AT(1) binding properties of pyrazolidine-3,5-diones and tetrahydropyridazine-3,6-diones with parent antihypertensive drug irbesartan.
Year : 2002
Volume : 45
Issue : 21
First Page : 4794
Last Page : 4798
Authors : Le Bourdonnec B, Cauvin C, Meulon E, Yous S, Goossens JF, Durant F, Houssin R, Hénichart JP.
Abstract : A new series of nonpeptide AT(1) receptor antagonists were recently developed, based on the structure of irbesartan (Le Bourdonnec et al. J. Med. Chem. 2000, 43, 2685-2697). The lead compound 1 displayed high selectivity for the AT(1) receptor subtype but lower binding affinity than irbesartan. As expected from molecular modeling studies, extension of the pyrazolidine-3,5-dione scaffold to the six-membered heterocycle tetrahydropyridazine-3,6-dione led to an enhancement of the binding affinity toward the AT(1) receptor.
|
Compound was evaluated for its binding affinity towards human Endothelin A receptor
|
None
|
0.0001
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-isoxazolyl biphenylsulfonamides as potent dual angiotensin II and endothelin A receptor antagonists.
Year : 2002
Volume : 45
Issue : 18
First Page : 3829
Last Page : 3835
Authors : Murugesan N, Tellew JE, Gu Z, Kunst BL, Fadnis L, Cornelius LA, Baska RA, Yang Y, Beyer SM, Monshizadegan H, Dickinson KE, Panchal B, Valentine MT, Chong S, Morrison RA, Carlson KE, Powell JR, Moreland S, Barrish JC, Kowala MC, Macor JE.
Abstract : The ET(A) receptor antagonist (2) (N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-[1,1'-biphenyl]-2-sulfonamide, BMS-193884) shares the same biphenyl core as a large number of AT(1) receptor antagonists, including irbesartan (3). Thus, it was hypothesized that merging the structural elements of 2 with those of the biphenyl AT(1) antagonists (e.g., irbesartan) would yield a compound with dual activity for both receptors. This strategy led to the design, synthesis, and discovery of (15) (4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-[1,1'-biphenyl]-2-sulfonamide, BMS-248360) as a potent and orally active dual antagonist of both AT(1) and ET(A) receptors. Compound 15 represents a new approach to treating hypertension.
|
Inhibitory activity against Ang II-induced proliferation of human aortic smooth muscle cells in a dose-dependent manner
|
Homo sapiens
|
320.0
nM
|
|
Journal : J. Med. Chem.
Title : Nonpeptide angiotensin II receptor antagonists: the next generation in antihypertensive therapy.
Year : 1996
Volume : 39
Issue : 3
First Page : 625
Last Page : 656
Authors : Wexler RR, Greenlee WJ, Irvin JD, Goldberg MR, Prendergast K, Smith RD, Timmermans PB.
|
Inhibition of AII(50 nM) induced intracellular [Ca2+] increase in PLC-PRF cells
|
Homo sapiens
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Comparison of 3D structures and AT(1) binding properties of pyrazolidine-3,5-diones and tetrahydropyridazine-3,6-diones with parent antihypertensive drug irbesartan.
Year : 2002
Volume : 45
Issue : 21
First Page : 4794
Last Page : 4798
Authors : Le Bourdonnec B, Cauvin C, Meulon E, Yous S, Goossens JF, Durant F, Houssin R, Hénichart JP.
Abstract : A new series of nonpeptide AT(1) receptor antagonists were recently developed, based on the structure of irbesartan (Le Bourdonnec et al. J. Med. Chem. 2000, 43, 2685-2697). The lead compound 1 displayed high selectivity for the AT(1) receptor subtype but lower binding affinity than irbesartan. As expected from molecular modeling studies, extension of the pyrazolidine-3,5-dione scaffold to the six-membered heterocycle tetrahydropyridazine-3,6-dione led to an enhancement of the binding affinity toward the AT(1) receptor.
|
In vitro antagonist activity, Inhibition of angiotensin II (50 nM) mediated increase in cytosolic [Ca2+] conc. in PLC-PRF-5 cells
|
None
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological evaluation of new pyrazolidine-3, 5-diones as AT(1) angiotensin II receptor antagonists.
Year : 2000
Volume : 43
Issue : 14
First Page : 2685
Last Page : 2697
Authors : Le Bourdonnec B, Meulon E, Yous S, Goossens JF, Houssin R, Hénichart JP.
Abstract : On the basis of the structure of the non-peptide receptor antagonist irbesartan, a new series of AT(1) ligands was designed. In these compounds the central imidazolone nucleus of irbesartan was replaced by a pyrazolidine-3,5-dione structure. The key intermediate N-alkylpyrazolidine-3,5-diones were synthesized according to a new and general method. The most active compounds possess a spirocyclopentane ring at position 4, a linear butyl chain at position 1, and the [2'-(5-tetrazolyl)biphenyl-4-yl]methyl or [2'-(benzoylaminosulfonyl)biphenyl-4-yl]methyl group at position 2. Affinity toward the AT(1) and AT(2) receptors was assessed by the ability of the compounds to competitively displace [(3)H]AII from its specific binding sites. The most active compounds, 28 and 48, displayed high affinity for the AT(1) receptor, good selectivity AT(1) versus AT(2), and potent in vitro antagonist activity.
|
Inhibitory activity against contractile response to angiotensin II (10 nM) of rabbit aortic rings
|
Oryctolagus cuniculus
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Development of tetrazole bioisosteres in angiotensin II antagonists
Year : 1994
Volume : 4
Issue : 1
First Page : 45
Last Page : 50
Authors : Ferrari B, Taillades J, Perreaut P, Bernhart C, Gougat J, Guiraudou P, Cazaubon C, Roccon A, Nisato D, Le Fur G, Breliere J
|
Compound was tested for its antagonistic activity against angiotensin II-induced contractions in rabbit aorta
|
Oryctolagus cuniculus
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Nonpeptide angiotensin II receptor antagonists: the next generation in antihypertensive therapy.
Year : 1996
Volume : 39
Issue : 3
First Page : 625
Last Page : 656
Authors : Wexler RR, Greenlee WJ, Irvin JD, Goldberg MR, Prendergast K, Smith RD, Timmermans PB.
|
Antagonistic activity through inhibition of A II induced contractions on rabbit aortic strips
|
Oryctolagus cuniculus
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : A new series of imidazolones: highly specific and potent nonpeptide AT1 angiotensin II receptor antagonists.
Year : 1993
Volume : 36
Issue : 22
First Page : 3371
Last Page : 3380
Authors : Bernhart CA, Perreaut PM, Ferrari BP, Muneaux YA, Assens JL, Clément J, Haudricourt F, Muneaux CF, Taillades JE, Vignal MA.
Abstract : Starting from the structure of the novel nonpeptide AT1 receptor antagonist DuP 753 (losartan), a new series of potent antagonists was designed. In these compounds the central imidazole nucleus was replaced by the dihydroimidazol-4-one structure. The most active compounds had a spirocyclopentane or a spirocyclohexane ring in position 5. Like the imidazole series, the best substituents were the linear butyl chain in position 1 and the [2'-(tetrazol-5-yl)biphenylyl]methyl group in position 3. Antagonistic activity was assessed by the ability of the compounds to competitively inhibit [125I]AII binding to the AT1 subtype receptor and to antagonize AII-induced contractions in rabbit aorta rings. The most active compounds had IC50 values in the nanomolar range. In conscious rats, compounds 4 and 21 antagonized the AII pressor response when administered orally. Compound 21 (SR 47436) was the most active; it was recently shown to also be active in cynomolgus monkeys both intravenously and orally. This molecule is now undergoing clinical trials for the treatment of hypertension.
|
Inhibitory concentration against angiotensin II receptor, type 1
|
Homo sapiens
|
0.8
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.
|
Binding affinity to angiotensin AT1 receptor in rat liver membranes
|
Rattus norvegicus
|
1.3
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Angiotensin II receptor type 1 (AT1) selective nonpeptidic antagonists--a perspective.
Year : 2010
Volume : 18
Issue : 24
First Page : 8418
Last Page : 8456
Authors : Naik P, Murumkar P, Giridhar R, Yadav MR.
Abstract : Hypertension is a major risk factor for human morbidity and mortality through its effects on target organs like heart, brain and kidneys. More intensive treatment for the effective control of blood pressure significantly reduces the morbidity and mortality. The renin angiotensin system (RAS) is a coordinated hormonal cascade of major clinical importance in the regulation of blood pressure. The principal effector peptide of RAS is angiotensin II, which acts by binding to one of the two major angiotensin II receptors AT(1) and AT(2). Angiotensin II through AT(1) receptor mediates vast majority of biologically detrimental actions. Nonpeptidic angiotensin II (AT(1)) antagonists are the most specific means to block the renin angiotensin enzymatic cascade available presently. Majority of AT(1) antagonists are based on modifications of losartan structure, the first clinically used AT(1) antagonist. In this review, a comprehensive presentation of the literature on AT(1) receptor antagonists has been given.
|
Binding affinity to angiotensin AT1 receptor
|
None
|
20.8
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Angiotensin II receptor type 1 (AT1) selective nonpeptidic antagonists--a perspective.
Year : 2010
Volume : 18
Issue : 24
First Page : 8418
Last Page : 8456
Authors : Naik P, Murumkar P, Giridhar R, Yadav MR.
Abstract : Hypertension is a major risk factor for human morbidity and mortality through its effects on target organs like heart, brain and kidneys. More intensive treatment for the effective control of blood pressure significantly reduces the morbidity and mortality. The renin angiotensin system (RAS) is a coordinated hormonal cascade of major clinical importance in the regulation of blood pressure. The principal effector peptide of RAS is angiotensin II, which acts by binding to one of the two major angiotensin II receptors AT(1) and AT(2). Angiotensin II through AT(1) receptor mediates vast majority of biologically detrimental actions. Nonpeptidic angiotensin II (AT(1)) antagonists are the most specific means to block the renin angiotensin enzymatic cascade available presently. Majority of AT(1) antagonists are based on modifications of losartan structure, the first clinically used AT(1) antagonist. In this review, a comprehensive presentation of the literature on AT(1) receptor antagonists has been given.
|
Displacement of [I125]angiotensin2 from AT1 receptor in Sprague-Dawley rat VSMC after 2.5 hrs by gamma spectrophotometry
|
Rattus norvegicus
|
0.58
nM
|
|
Displacement of [I125]angiotensin2 from AT1 receptor in Sprague-Dawley rat VSMC after 2.5 hrs by gamma spectrophotometry
|
Rattus norvegicus
|
0.41
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of novel potent angiotensin II receptor antagonists with anti-hypertension effect.
Year : 2012
Volume : 20
Issue : 8
First Page : 2747
Last Page : 2761
Authors : Nie YY, Da YJ, Zheng H, Yang XX, Jia L, Wen CH, Liang LS, Tian J, Chen ZL.
Abstract : A series of novel angiotensin II type 1 receptor antagonists were prepared. Radioligand binding assay suggested that compounds 1b and 1c could be recognized by the AT(1) receptor with an IC(50) value of 1.6 ± 0.09 nM and 2.64 ± 0.7 nM, respectively. In vivo anti-hypertension experiments showed that compounds (1a, 1b, 1c, 1e) elicited a significant decrease in SBP and DBP of spontaneous hypertensive rats (SHRs). The antihypertensive effects maintained for 10 h, which indicated that these compounds had a favorable blood pressure-lowering effect. Acute toxicity testing suggested that the LD(50) value of compound 1b was 2316.8 mg/kg which was lower than valsartan (LD(50)=307.50 mg/kg) but higher than losartan (LD(50)=2248 mg/kg). So they could be considered as novel anti-hypertension candidates and deserved for further investigation.
|
Binding affinity to AT1 receptor
|
None
|
0.8
nM
|
|
Journal : J. Med. Chem.
Title : Chemokine receptor antagonists.
Year : 2012
Volume : 55
Issue : 22
First Page : 9363
Last Page : 9392
Authors : Pease J, Horuk R.
|
Displacement of [125I]Angiotensin-2 from angiotensin AT1 receptor in Sprague-Dawley rat VSMC after 60 mins by gamma counting
|
Rattus norvegicus
|
2.75
nM
|
|
Displacement of [125I]Angiotensin-2 from angiotensin AT1 receptor in Sprague-Dawley rat VSMC after 60 mins by gamma counting
|
Rattus norvegicus
|
3.11
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of new fluorine substituted derivatives as angiotensin II receptor antagonists with anti-hypertension and anti-tumor effects.
Year : 2012
Volume : 20
Issue : 24
First Page : 7101
Last Page : 7111
Authors : Da YJ, Yuan WD, Xin T, Nie YY, Ye Y, Yan YJ, Liang LS, Chen ZL.
Abstract : The synthesis and pharmaceutical activity of new potent non-tetrazole angiotensin II (Ang II) receptor antagonists were described. These compounds were fluorine substituted derivatives of Losartan, Valsartan and Irbesartan with carboxylic acid group as replacements to the known potent tetrazole moiety at the 2'-biphenyl position. Their activities were evaluated by Ang II receptor binding assay as well as by in vivo assay. All of the synthesized compounds showed nanomolar affinity for the AT(1) receptor subtype. The vivo biological evaluation showed that compounds 1a, 2 and 4 produced a dose-dependent antihypertensive effect both in spontaneously hypertensive rats (SHR) and renal hypertensive rats (RHR). Compound 4 especially showed an efficient and long-lasting effect in reducing blood pressure which can last more than 24 h at dose of 10 mg/kg in SHR, which was much better than control Losartan and Valsartan. Compound 4 can also inhibit the prostate cancer in vitro and in vivo. So compound 4 was selected for in-depth investigation as potent, novel and long-lasting non-tetrazole anti-hypertension and anti-tumor drug candidate.
|
Inhibition of human MATE1-mediated ASP+ uptake expressed in HEK293 cells at 20 uM after 1.5 mins by fluorescence assay
|
Homo sapiens
|
15.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling.
Year : 2013
Volume : 56
Issue : 3
First Page : 781
Last Page : 795
Authors : Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM.
Abstract : The human multidrug and toxin extrusion (MATE) transporter 1 contributes to the tissue distribution and excretion of many drugs. Inhibition of MATE1 may result in potential drug-drug interactions (DDIs) and alterations in drug exposure and accumulation in various tissues. The primary goals of this project were to identify MATE1 inhibitors with clinical importance or in vitro utility and to elucidate the physicochemical properties that differ between MATE1 and OCT2 inhibitors. Using a fluorescence assay of ASP(+) uptake in cells stably expressing MATE1, over 900 prescription drugs were screened and 84 potential MATE1 inhibitors were found. We identified several MATE1 selective inhibitors including four FDA-approved medications that may be clinically relevant MATE1 inhibitors and could cause a clinical DDI. In parallel, a QSAR model identified distinct molecular properties of MATE1 versus OCT2 inhibitors and was used to screen the DrugBank in silico library for new hits in a larger chemical space.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
76.05
%
|
|
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
|
47.18
%
|
|
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.
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Displacement of 125I-Ang2 from AT1 receptor in SPF Sprague-Dawley rat vascular smooth muscle cell membranes after 150 mins by gamma counting method
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Rattus norvegicus
|
1.05
nM
|
|
Displacement of 125I-Ang2 from AT1 receptor in SPF Sprague-Dawley rat vascular smooth muscle cell membranes after 150 mins by gamma counting method
|
Rattus norvegicus
|
1.46
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and evaluation of novel potent angiotensin II receptor 1 antagonists.
Year : 2016
Volume : 123
First Page : 115
Last Page : 127
Authors : Bao X, Zhu W, Yuan W, Zhu X, Yan Y, Tang H, Chen Z.
Abstract : A series of new angiotensin II (Ang II) receptor 1 antagonists were designed, synthesized and evaluated. All compounds showed nanomolar affinities for the angiotensin II type 1 receptor in radioligand binding assays and could reduce blood pressure significantly in spontaneously hypertensive rats(SHRs). From which, compound 2b displayed higher affinity binding to angiotensin II type 1 receptor at the same order of magnitude to irbesartan with an IC50 value of 1.26 ± 0.08 nM in radioligand binding assays. 2b showed an efficient and long-lasting effect in reducing blood pressure, the maximal reducing responses were 40.62 ± 4.08 mmHg of MBP at 15 mg/kg and 28.39 ± 2.09 mmHg at 10 mg/kg in SHRs, 39.56 ± 4.83 mmHg at 15 mg/kg and 29.05 ± 2.20 mmHg at 10 mg/kg in RHRs, the significant antihypertensive effect lasted beyond 12 h both in SHRs and in RHRs. In the single-dose pharmacokinetic experiments, compound 2b could be absorbed efficiently and metabolized smoothly in Wistar rats after oral administration. The values of Cmax, Tmax, AUC0-72 and MRT0-72 were 885.61 ± 432.7 ng/mL, 5.67 ± 1.51 h, 6110.28 ± 7398.33 ng/mL h and 7.87 ± 2.30 h at 10 mg/kg, 2945.55 ± 1543.67 ng/mL, 4.33 ± 0.82 h, 26473.62 ± 12217.16 ng/mL h and 10.24 ± 6.94 h at 15 mg/kg, 5759.03 ± 1331.75 ng/mL, 5 ± 1.10 h, 89488.44 ± 18413.15 ng/mL·h and 12.89 ± 2.0 h at 30 mg/kg respectively. The T1/2 values of the three groups were similar, about 9-10 h. Compound 2b was distributed into tissues rapidly and extensively after oral administration. The level of it was the highest in the liver, followed by in spleen, kidney, and the lowest in brain. The acute toxicity assays of 2b proved its low acute toxicity with an LD50 value of 1551.71 mg/kg, and no toxicity reaction appeared at dose of 1200.00 mg/kg. These encouraging results make compound 2b an effective, long-lasting and safe anti-hypertensive drug candidate and worthy of further investigation.
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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
|
6.34
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-3.35
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
7.4
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
1.45
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
6.33
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
-0.2
%
|
|
|
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
|
0.28
%
|
|
|
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
|
-3.98
%
|
|
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
|
13.92
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
9.227
%
|
|
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
|
-0.15
%
|
|
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
|
0.11
%
|
|
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
|
-0.15
%
|
|
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
|
0.11
%
|
|
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 [3H]-U46619 binding to TxA2 receptor in human platelet suspension at 0.3 uM incubated for 30 mins by liquid scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Progress toward a Glycoprotein VI Modulator for the Treatment of Thrombosis.
Year : 2020
Volume : 63
Issue : 21
First Page : 12213
Last Page : 12242
Authors : Foster H,Wilson C,Philippou H,Foster R
Abstract : Pathogenic thrombus formation accounts for the etiology of many serious conditions including myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. Despite the development of numerous anticoagulants and antiplatelet agents, the mortality rate associated with these diseases remains high. In recent years, however, significant epidemiological evidence and clinical models have emerged to suggest that modulation of the glycoprotein VI (GPVI) platelet receptor could be harnessed as a novel antiplatelet strategy. As such, many peptidic agents have been described in the past decade, while more recent efforts have focused on the development of small molecule modulators. Herein the rationale for targeting GPVI is summarized and the published GPVI modulators are reviewed, with particular focus on small molecules. A qualitative pharmacophore hypothesis for small molecule ligands at GPVI is also presented.
|
Agonist activity at human BLT2 overexpressed in CHO-K1 cells assessed as accumulation of inositol monophosphate measured after 90 mins by HTRF assay
|
Homo sapiens
|
410.0
nM
|
|
|
Antagonist activity at human AT1 overexpressed in CHO-K1 cells in presence of 10 nM [Val5-angiotensin II measured after 90 mins by HTRF based IP-one assay
|
Homo sapiens
|
6.0
nM
|
|
