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1.
Bioorg Med Chem Lett ; 2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30392779

RESUMO

Synthesis and structure-activity relationships (SAR) of a novel series of benzodiazepinedione-based inhibitors of Clostridium difficile toxin B (TcdB) are described. Compounds demonstrating low nanomolar affinity for TcdB, and which possess improved stability in mouse plasma vs. earlier compounds from this series, have been identified. Optimized compound 11d demonstrates a good pharmacokinetic (PK) profile in mouse and hamster and is efficacious in a hamster survival model of Clostridium difficile infection.

2.
Artigo em Inglês | MEDLINE | ID: mdl-29483125

RESUMO

Clostridium difficile infection (CDI) is the leading cause of hospital-acquired infectious diarrhea, with significant morbidity, mortality, and associated health care costs. The major risk factor for CDI is antimicrobial therapy, which disrupts the normal gut microbiota and allows C. difficile to flourish. Treatment of CDI with antimicrobials is generally effective in the short term, but recurrent infections are frequent and problematic, indicating that improved treatment options are necessary. Symptoms of disease are largely due to two homologous toxins, TcdA and TcdB, which are glucosyltransferases that inhibit host Rho GTPases. As the normal gut microbiota is an important component of resistance to CDI, our goal was to develop an effective nonantimicrobial therapy. Here, we report a highly potent small-molecule inhibitor (VB-82252) of TcdA and TcdB. This compound inhibits the UDP-glucose hydrolysis activity of TcdB and protects cells from intoxication after challenge with either toxin. Oral dosing of the inhibitor prevented inflammation in a murine intrarectal toxin challenge model. In a murine model of recurrent CDI, the inhibitor reduced weight loss and gut inflammation during acute disease and did not cause the recurrent disease that was observed with vancomycin treatment. Lastly, the inhibitor demonstrated efficacy similar to that of vancomycin in a hamster disease model. Overall, these results demonstrate that small-molecule inhibition of C. difficile toxin UDP-glucose hydrolysis activity is a promising nonantimicrobial approach to the treatment of CDI.

3.
Bioorg Med Chem Lett ; 28(4): 756-761, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29331267

RESUMO

The discovery, synthesis and preliminary structure-activity relationship (SAR) of a novel class of inhibitors of Clostridium difficile (C. difficile) toxin B (TcdB) is described. A high throughput screening (HTS) campaign resulted in the identification of moderately active screening hits 1-5 the most potent of which was compound 1 (IC50 = 0.77 µM). In silico docking of an early analog offered suggestions for structural modification which resulted in the design and synthesis of highly potent analogs 13j(IC50 = 1 nM) and 13 l(IC50 = 7 nM) which were chosen as leads for further optimization.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Toxinas Bacterianas/antagonistas & inibidores , Clostridium difficile/efeitos dos fármacos , Nucleotidases/antagonistas & inibidores , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacocinética , Apoptose/efeitos dos fármacos , Células CHO , Cricetulus , Estabilidade de Medicamentos , Enterotoxinas/antagonistas & inibidores , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade
4.
Proc Natl Acad Sci U S A ; 111(50): E5455-62, 2014 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-25453091

RESUMO

Drug discovery for malaria has been transformed in the last 5 years by the discovery of many new lead compounds identified by phenotypic screening. The process of developing these compounds as drug leads and studying the cellular responses they induce is revealing new targets that regulate key processes in the Plasmodium parasites that cause malaria. We disclose herein that the clinical candidate (+)-SJ733 acts upon one of these targets, ATP4. ATP4 is thought to be a cation-transporting ATPase responsible for maintaining low intracellular Na(+) levels in the parasite. Treatment of parasitized erythrocytes with (+)-SJ733 in vitro caused a rapid perturbation of Na(+) homeostasis in the parasite. This perturbation was followed by profound physical changes in the infected cells, including increased membrane rigidity and externalization of phosphatidylserine, consistent with eryptosis (erythrocyte suicide) or senescence. These changes are proposed to underpin the rapid (+)-SJ733-induced clearance of parasites seen in vivo. Plasmodium falciparum ATPase 4 (pfatp4) mutations that confer resistance to (+)-SJ733 carry a high fitness cost. The speed with which (+)-SJ733 kills parasites and the high fitness cost associated with resistance-conferring mutations appear to slow and suppress the selection of highly drug-resistant mutants in vivo. Together, our data suggest that inhibitors of PfATP4 have highly attractive features for fast-acting antimalarials to be used in the global eradication campaign.


Assuntos
Antimaláricos/farmacologia , ATPases Transportadoras de Cálcio/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Isoquinolinas/farmacologia , Malária/tratamento farmacológico , Modelos Moleculares , Plasmodium/efeitos dos fármacos , Antimaláricos/farmacocinética , ATPases Transportadoras de Cálcio/genética , Senescência Celular/efeitos dos fármacos , Descoberta de Drogas , Resistência a Medicamentos/genética , Eritrócitos/efeitos dos fármacos , Citometria de Fluxo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Ensaios de Triagem em Larga Escala , Isoquinolinas/farmacocinética , Estrutura Molecular
5.
Bioorg Med Chem Lett ; 23(13): 3914-9, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23683593

RESUMO

The 5-HT2C receptor has been implicated as a critical regulator of appetite. Small molecule activation of the 5-HT2C receptor has been shown to affect food intake and regulate body weight gain in rodent models and more recently in human clinical trials. Therefore, 5-HT2C is a well validated target for anti-obesity therapy. The synthesis and structure-activity relationships of a series of novel tetrahydropyrazinoisoquinolinone 5-HT2C receptor agonists are presented. Several members of this series were identified as potent 5-HT2C receptor agonists with high functional selectivity against the 5-HT2A and 5-HT2B receptors and reduced food intake in an acute rat feeding model upon oral dosing.


Assuntos
Isoquinolinas/farmacologia , Pirazinas/farmacologia , Receptor 5-HT2C de Serotonina/metabolismo , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Modelos Moleculares , Estrutura Molecular , Pirazinas/síntese química , Pirazinas/química , Ratos , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 21(24): 7516-21, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-22041058

RESUMO

The design, synthesis and SAR of a novel class of valerolactam-based arylsulfonamides as potent and selective FXa inhibitors is reported. The arylsulfonamide-valerolactam scaffold was derived based on the proposed bioisosterism to the arylcyanoguanidine-caprolactam core in known FXa inhibitors. The SAR study led to compound 46 as the most potent FXa inhibitor in this series, with an IC(50) of 7 nM and EC(2×PT) of 1.7 µM. The X-ray structure of compound 40 bound to FXa shows that the sulfonamide-valerolactam scaffold anchors the aryl group in the S1 and the novel acylcytisine pharmacophore in the S4 pockets.


Assuntos
Anticoagulantes/química , Inibidores do Fator Xa , Piperidonas/química , Inibidores de Serino Proteinase/química , Anticoagulantes/síntese química , Anticoagulantes/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Fator Xa/metabolismo , Humanos , Lactamas/química , Conformação Molecular , Piperidonas/síntese química , Piperidonas/farmacologia , Estrutura Terciária de Proteína , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/farmacologia , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 19(24): 6882-9, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-19896847

RESUMO

We report the design and synthesis of a novel class of N,N'-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC(50)=4 nM, EC(2xPT)=7 microM). However, the potent CYP3A4 inhibition activity (IC(50)=0.3 microM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC(50)=9 nM, EC(2xPT)=2.5 microM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models.


Assuntos
Anticoagulantes/química , Inibidores do Fator Xa , Guanidinas/química , Inibidores de Serino Proteinase/química , Anticoagulantes/farmacologia , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Descoberta de Drogas , Guanidinas/farmacologia , Humanos , Concentração Inibidora 50 , Inibidores de Serino Proteinase/farmacologia , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 19(15): 4034-41, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19541481

RESUMO

The N,N'-disubstituted cyanoguanidine is an excellent bioisostere of the thiourea and ketene aminal functional groups. We report the design and synthesis of a novel class of cyanoguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The SAR studies led to the discovery of compound 4 (BMS-269223, K(i)=6.5nM, EC(2xPT)=32muM) as a selective, orally bioavailable FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models. The X-ray crystal structure of 4 bound in FXa is presented and key ligand-protein interactions are discussed.


Assuntos
Antitrombina III/farmacologia , Benzofuranos/farmacologia , Guanidinas/química , Lactamas/química , Administração Oral , Animais , Antitrombina III/química , Benzofuranos/química , Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Cães , Haplorrinos , Humanos , Concentração Inibidora 50 , Cinética , Lactamas/farmacologia , Ligantes , Modelos Químicos , Ratos , Relação Estrutura-Atividade , Tioureia/química
9.
J Med Chem ; 51(23): 7541-51, 2008 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-18998662

RESUMO

An indole-based P1 moiety was incorporated into a previously established factor Xa inhibitor series. The indole group was designed to hydrogen-bond with the carbonyl of Gly218, while its 3-methyl or 3-chloro substituent was intended to interact with Tyr228. These interactions were subsequently observed in the X-ray crystal structure of compound 18. SAR studies led to the identification of compound 20 as the most potent FXa inhibitor in this series (IC(50) = 2.4 nM, EC(2xPT) = 1.2 microM). An in-depth energetic analysis suggests that the increased binding energy of 3-chloroindole-versus 3-methylindole-containing compounds in this series is due primarily to (a) the more hydrophobic nature of chloro- versus methyl-containing compounds and (b) an increased interaction of 3-chloroindole versus 3-methylindole with Gly218 backbone. The stronger hydrophobicity of chloro- versus methyl-substituted aromatics may partly explain the general preference for chloro- versus methyl-substituted P1 groups in FXa, which extends beyond the current series.


Assuntos
Desenho de Drogas , Inibidores Enzimáticos , Inibidores do Fator Xa , Indóis , Teoria Quântica , Animais , Sítios de Ligação/efeitos dos fármacos , Simulação por Computador , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fator Xa/efeitos dos fármacos , Humanos , Ligações de Hidrogênio , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Camundongos , Modelos Químicos , Modelos Moleculares , Relação Estrutura-Atividade , Análise de Sobrevida , Peçonhas/farmacologia , Trombose Venosa/tratamento farmacológico , Trombose Venosa/enzimologia
10.
Bioorg Med Chem Lett ; 18(16): 4696-9, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18644722

RESUMO

A series of acylguanidine derivatives were prepared and investigated as inhibitors of Factor Xa (FXa). These compounds were made by guanidine acylation with carboxylic acids using carbonyl diimidazole (CDI) as the coupling reagent. Conditions for the rapid synthesis and purification of these compounds are described along with their ability to inhibit FXa. The best FXa inhibitor is 1 with a FXa IC(50) of 6 nM.


Assuntos
Antitrombina III/síntese química , Antitrombina III/farmacologia , Química Farmacêutica/métodos , Fator Xa/química , Guanidinas/síntese química , Guanidinas/farmacologia , Anticoagulantes/síntese química , Anticoagulantes/farmacologia , Coagulação Sanguínea , Ácidos Carboxílicos/química , Desenho de Drogas , Guanina/química , Humanos , Imidazóis/química , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular
11.
J Med Chem ; 51(9): 2722-33, 2008 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-18412317

RESUMO

3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950). Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.


Assuntos
Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/síntese química , Pirimidinas/síntese química , Triazóis/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Colesterol/biossíntese , Colesterol/sangue , Cristalografia por Raios X , Cães , Feminino , Cobaias , Haplorrinos , Humanos , Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Técnicas In Vitro , Fígado/efeitos dos fármacos , Fígado/metabolismo , Modelos Moleculares , Células Musculares/citologia , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , Pirimidinas/farmacologia , Pirimidinas/toxicidade , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/farmacologia , Triazóis/toxicidade
12.
J Pharmacol Exp Ther ; 324(2): 576-86, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17986646

RESUMO

Statins, because of their excellent efficacy and manageable safety profile, represent a key component in the current armamentarium for the treatment of hypercholesterolemia. Nonetheless, myopathy remains a safety concern for this important drug class. Cerivastatin was withdrawn from the market for myotoxicity safety concerns. BMS-423526 [{(3R,5S)-7-[4-(4-fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-3-yl]-3,5-dihydroxy-heptenoic acid} sodium salt], similar to cerivastatin in potency and lipophilicity, was terminated in early clinical development due to an unacceptable myotoxicity profile. In this report, we describe the guinea pig as a model of statin-induced cholesterol lowering and myotoxicity and show that this model can distinguish statins with unacceptable myotoxicity profiles from statins with acceptable safety profiles. In our guinea pig model, both cerivastatin and BMS-423526 induced myotoxicity at doses near the ED(50) for total cholesterol (TC) lowering in plasma. In contrast, wide differences between myotoxic and TC-lowering doses were established for the currently marketed, more hydrophilic statins, pravastatin, rosuvastatin, and atorvastatin. This in vivo model compared favorably to an in vitro model, which used statin inhibition of cholesterol synthesis in rat hepatocytes and L6 myoblasts as surrogates of potential efficacy and toxicity, respectively. Our conclusion is that the guinea pig is a useful preclinical in vivo model for demonstrating whether a statin is likely to have an acceptable therapeutic safety margin.


Assuntos
Cobaias/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Modelos Animais , Animais , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos/métodos , Cobaias/sangue , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Ratos , Ratos Sprague-Dawley
13.
Bioorg Med Chem Lett ; 17(21): 5952-8, 2007 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17855089

RESUMO

The design and synthesis of a novel class of amino(methyl) pyrrolidine-based sulfonamides as potent and selective FXa inhibitors is reported. The amino(methyl) pyrrolidine scaffolds were designed based on the proposed bioisosterism to the piperazine core in known FXa inhibitors. The SAR study led to compound 15 as the most potent FXa inhibitor in this series, with an IC(50) of 5.5 nM and PT EC(2x) of 1.7 microM. The proposed binding models show that the pyrrolidine cores are in van der Waals contact with the enzyme surface, and the flexibility of amino(methyl) pyrrolidines allows the two nitrogen atoms to anchor both the P1 and P4 groups to fit similarly in the S1 and S4 pockets.


Assuntos
Inibidores do Fator Xa , Pirrolidinas/química , Inibidores de Serino Proteinase/farmacologia , Modelos Moleculares , Inibidores de Serino Proteinase/química , Relação Estrutura-Atividade
15.
Bioorg Med Chem Lett ; 15(11): 2749-51, 2005 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-15878269

RESUMO

The preferred absolute configuration of two series of F(1)F(0)-ATP synthase inhibitors was determined. Although the configuration of the active enantiomer in each series is different, each series presents the same 'triaryl' pharmacophore to the enzyme binding site.


Assuntos
Mitocôndrias/enzimologia , ATPases Translocadoras de Prótons/metabolismo , Sítios de Ligação , Modelos Moleculares , Estereoisomerismo
16.
Bioorg Med Chem Lett ; 14(4): 1031-4, 2004 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-15013017

RESUMO

A series of benzodiazepine-based inhibitors of mitochondrial F(1)F(0) ATP hydrolase were prepared and evaluated for their ability to selectively inhibit the enzyme in the forward direction. Compounds from this series showed excellent potency and selectivity for ATP hydrolase versus ATP synthase, suggesting a potentially beneficial profile useful for the treatment of ischemic heart disease.


Assuntos
Trifosfato de Adenosina/metabolismo , Benzodiazepinas/farmacologia , Inibidores Enzimáticos/farmacologia , Mitocôndrias/enzimologia , ATPases Mitocondriais Próton-Translocadoras/antagonistas & inibidores , Animais , Benzodiazepinas/síntese química , Bovinos , Inibidores Enzimáticos/síntese química , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Relação Estrutura-Atividade
17.
Bioorg Med Chem Lett ; 14(4): 1027-30, 2004 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-15013016

RESUMO

A series of substituted guanidine derivatives were prepared and evaluated as potent and selective inhibitors of mitochondrial F(1)F(0) ATP hydrolase. The initial thiourethane derived lead molecules possessed intriguing in vitro pharmacological profiles, though contained moieties considered non-drug-like. Analogue synthesis efforts led to compounds with maintained potency and superior physical properties. Small molecules in this series which potently and selectivity inhibit ATP hydrolase and not ATP synthase may have utility as cardioprotective agents.


Assuntos
Trifosfato de Adenosina/metabolismo , Inibidores Enzimáticos/farmacologia , Guanidinas/farmacologia , Mitocôndrias/enzimologia , ATPases Mitocondriais Próton-Translocadoras/antagonistas & inibidores , Animais , Bovinos , Inibidores Enzimáticos/síntese química , Guanidinas/síntese química , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Relação Estrutura-Atividade
18.
J Org Chem ; 69(1): 188-91, 2004 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-14703396

RESUMO

N,N'-Disubstituted ketene aminals are bioisosteres of thioureas and are useful building blocks in many synthetic operations. A convenient one-pot synthesis of N,N'-disubstituted ketene aminals from activated methylene compounds and isothiocyanates is described. Most of these aminals exist in rotameric equilibrium around the central C=C bonds in solution, and the rotamers are stabilized by intramolecular hydrogen bonding both in solution and in solid states.

19.
Bioorg Med Chem Lett ; 14(1): 99-102, 2004 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-14684307

RESUMO

Class III anti-arrhythmic drugs (e.g., dofetilide) prolong cardiac action potential duration (APD) by blocking the fast component of the delayed rectifier potassium current (I(Kr)). The block of I(Kr) can result in life threatening ventricular arrhythmias (i.e., torsades de pointes). Unlike I(Kr), the role of the slow component of the delayed rectifier potassium current (I(Ks)) becomes significant only at faster heart rate. Therefore selective blockers of I(Ks) could prolong APD with a reduced propensity to cause pro-arrhythmic side effects. This report describes structure-activity relationships (SARs) of a series of I(Ks) inhibitors derived from 6-alkoxytetralones with good in vitro activity (IC(50) > or =30 nM) and up to 40-fold I(Ks)/I(Kr) selectivity.


Assuntos
Amino Álcoois/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/fisiologia , Tetra-Hidronaftalenos/farmacologia , Amino Álcoois/química , Animais , Canais de Potássio de Retificação Tardia , Cobaias , Cetonas/química , Cetonas/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Bloqueadores dos Canais de Potássio/química , Tetra-Hidronaftalenos/química
20.
Bioorg Med Chem Lett ; 12(4): 517-20, 2002 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-11844662

RESUMO

A number of 4'-heterocyclic biphenylsulfonamide derivatives, formally derived from BMS-193884 (1) by replacing the oxazole ring with other heterocyclic rings, are potent and selective endothelin A (ET(A)) receptor antagonists. Among the analogues examined, the pyrimidine derivative 18 is the most potent (K(i)=0.9 nM) and selective for the ET(A) receptor, approximately equivalent to 1.


Assuntos
Compostos de Bifenilo/síntese química , Antagonistas dos Receptores de Endotelina , Sulfonamidas/síntese química , Animais , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Células CHO , Cricetinae , Humanos , Ligação Proteica , Receptor de Endotelina A , Receptores de Endotelina/genética , Receptores de Endotelina/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Transfecção
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