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1.
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
2.
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
3.
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
4.
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
5.
Bioorg Med Chem Lett ; 17(23): 6476-80, 2007 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-17937986

RESUMO

The synthesis and structure-activity relationships of novel dipeptidyl peptidase IV inhibitors replacing the classical cyanopyrrolidine P1 group with other small nitrogen heterocycles are described. A unique potency enhancement was achieved with beta-branched natural and unnatural amino acids, particularly adamantylglycines, linked to a (2S,3R)-2,3-methanopyrrolidine based scaffold.


Assuntos
Dipeptídeos/química , Inibidores da Dipeptidil Peptidase IV , Inibidores da Dipeptidil Peptidase IV/química , Dipeptídeos/farmacologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Nitrilos/química , Nitrilos/farmacologia , Relação Estrutura-Atividade
6.
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
8.
Bioorg Med Chem Lett ; 16(18): 4796-9, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16870436

RESUMO

A series of potent inhibitors of the sodium hydrogen exchanger-1 (NHE-1) is described. Structure-activity relationships identified the 3-methyl-4-fluoro analog 9t as a highly potent (IC50 = 0.0065 microM) and selective (NHE-2/NHE-1=1400) non-acylguanidine NHE-1 inhibitor. Pharmacokinetic studies showed that compound 9t has an oral bioavailability of 52% and a plasma half life of 1.5 h in rats. Because of its promising potency, selectivity, and a good pharmacokinetic profile, compound 9t was selected for further studies.


Assuntos
Piperidinas/química , Piperidinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Trocadores de Sódio-Hidrogênio/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Concentração Inibidora 50 , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/farmacocinética , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos , Trocadores de Sódio-Hidrogênio/metabolismo , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 15(5): 1435-40, 2005 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-15713402

RESUMO

A series of inhibitors of mammalian 15-lipoxygenase based on tryptamine and homotryptamine scaffolds is described. Compounds with aryl substituents at C-2 of the indole core of tryptamine and homotryptamine sulfonamides (e.g., 37a-p) proved to be potent inhibitors of the isolated enzyme. Selected compounds also demonstrated desirable inhibition selectivities over isozymes 5- and P-12-LO.


Assuntos
Inibidores Enzimáticos/farmacologia , Inibidores de Lipoxigenase , Sulfonamidas/farmacologia , Triptaminas/química , Animais , Inibidores Enzimáticos/química , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/química
11.
Am J Physiol Heart Circ Physiol ; 287(4): H1747-55, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15371268

RESUMO

Mitochondrial F(1)F(0)-ATPase normally synthesizes ATP in the heart, but under ischemic conditions this enzyme paradoxically causes ATP hydrolysis. Nonselective inhibitors of this enzyme (aurovertin, oligomycin) inhibit ATP synthesis in normal tissue but also inhibit ATP hydrolysis in ischemic myocardium. We characterized the profile of aurovertin and oligomycin in ischemic and nonischemic rat myocardium and compared this with the profile of BMS-199264, which only inhibits F(1)F(0)-ATP hydrolase activity. In isolated rat hearts, aurovertin (1-10 microM) and oligomycin (10 microM), at concentrations inhibiting ATPase activity, reduced ATP concentration and contractile function in the nonischemic heart but significantly reduced the rate of ATP depletion during ischemia. They also inhibited recovery of reperfusion ATP and contractile function, consistent with nonselective F(1)F(0)-ATPase inhibitory activity, which suggests that upon reperfusion, the hydrolase activity switches back to ATP synthesis. BMS-199264 inhibits F(1)F(0) hydrolase activity in submitochondrial particles with no effect on ATP synthase activity. BMS-199264 (1-10 microM) conserved ATP in rat hearts during ischemia while having no effect on preischemic contractile function or ATP concentration. Reperfusion ATP levels were replenished faster and necrosis was reduced by BMS-199264. ATP hydrolase activity ex vivo was selectively inhibited by BMS-199264. Therefore, excessive ATP hydrolysis by F(1)F(0)-ATPase contributes to the decline in cardiac energy reserve during ischemia and selective inhibition of ATP hydrolase activity can protect ischemic myocardium.


Assuntos
Trifosfato de Adenosina/metabolismo , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Isquemia Miocárdica/metabolismo , ATPases Translocadoras de Prótons/metabolismo , Animais , Aurovertinas/química , Aurovertinas/farmacologia , Sobrevivência Celular/fisiologia , Hidrólise , Imidazóis/química , Masculino , Mitocôndrias/enzimologia , Miocárdio/citologia , Miocárdio/metabolismo , Oligomicinas/química , Oligomicinas/farmacologia , ATPases Translocadoras de Prótons/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Desacopladores/química , Desacopladores/farmacologia
12.
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
13.
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
14.
J Med Chem ; 47(5): 1081-4, 2004 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-14971888

RESUMO

In this paper we show that 4-aryl-CH2-imidazole-substituted benzopyran compounds with 3S,4R-stereochemistry are cardioprotective by inhibiting the F1F0 mitochondrial ATP hydrolase. Compounds (e.g., 13) with 3R,4S-stereochemistry act as mitochondrial KATP openers. This resulted from an inversion of stereochemistry for the F1F0 mitochondrial ATP hydrolase vs mitochondrial KATP. Structure-activity relationships for the inhibition of mitochondrial ATP hydrolase are also delineated. It is not clear how 13 (3R,4S) can selectively inhibit the hydrolytic activity of the F1F0 mitochondrial enzyme without interfering with the synthase activity.


Assuntos
Benzopiranos/síntese química , Cardiotônicos/síntese química , Imidazóis/síntese química , ATPases Mitocondriais Próton-Translocadoras/antagonistas & inibidores , Trifosfato de Adenosina/biossíntese , Trifosfato de Adenosina/metabolismo , Animais , Benzopiranos/química , Benzopiranos/farmacologia , Cardiotônicos/química , Cardiotônicos/farmacologia , Bovinos , Citrato (si)-Sintase/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Hidrólise , Imidazóis/química , Imidazóis/farmacologia , Técnicas In Vitro , Contração Miocárdica/efeitos dos fármacos , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
15.
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.

16.
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
17.
Bioorg Med Chem Lett ; 14(1): 177-80, 2004 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-14684323

RESUMO

Inhibition of the sodium hydrogen exchanger isoform-1 (NHE-1) has been shown to limit damage to the myocardium under ischemic conditions in animals. While most known NHE-1 inhibitors are acylguanidines, this report describes the design and synthesis of a series of heterocyclic inhibitors of NHE-1 including aminoimidazoles with undiminished in vitro activity and oral bioavailability.


Assuntos
Proteínas de Transporte de Cátions/antagonistas & inibidores , Guanidinas/administração & dosagem , Imidazóis/administração & dosagem , Proteínas de Membrana/antagonistas & inibidores , Trocadores de Sódio-Hidrogênio/antagonistas & inibidores , Administração Oral , Disponibilidade Biológica , Proteínas de Transporte de Cátions/metabolismo , Linhagem Celular , Guanidinas/química , Guanidinas/farmacocinética , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Proteínas de Membrana/metabolismo , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Trocador 1 de Sódio-Hidrogênio , Trocadores de Sódio-Hidrogênio/metabolismo , Estereoisomerismo
18.
Cardiovasc Drug Rev ; 20(2): 121-36, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12177690

RESUMO

ATP-sensitive potassium channel (K(ATP)) openers as a class protect ischemic myocardium. The protective effects are independent of vasodilator activity and effects on action potential shortening, actions typically associated with sarcolemmal K(ATP) activation. BMS-191095 is a novel mitochondrial K(ATP) opener which protects ischemic myocardium while having no electrophysiologic or vasodilator effects (determined in vitro and in vivo). The cardioprotective effects were determined in isolated rat hearts subjected to ischemia and reperfusion. Protective effects were deduced from increased time to contracture formation during ischemia, improved reperfusion recovery of contractile function, and reduced reperfusion LDH release. The cardioprotective effects of BMS-191095 were observed at concentrations at which this compound selectively opened cardiac mitochondrial K(ATP) channels. This effect was consistent with the pharmacologic profile of this agent. The protective effects were abolished by mitochondrial K(ATP) inhibition. Unlike first-generation K(ATP) openers, BMS-191095 is expected to protect ischemic myocardium with little hemodynamic sequelae and without any proarrhythmic potential. BMS-191095 is potentially useful clinically as a cardioprotective agent. It is also a useful tool for basic research.


Assuntos
Benzopiranos/farmacologia , Cardiotônicos/farmacologia , Imidazóis/farmacologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Isquemia Miocárdica/tratamento farmacológico , Canais de Potássio/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Benzopiranos/farmacocinética , Benzopiranos/uso terapêutico , Disponibilidade Biológica , Cardiotônicos/farmacocinética , Cardiotônicos/uso terapêutico , Coração/efeitos dos fármacos , Coração/fisiologia , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Mitocôndrias Cardíacas/fisiologia , Isquemia Miocárdica/metabolismo , Músculos Papilares/efeitos dos fármacos , Canais de Potássio/fisiologia , Relação Estrutura-Atividade , Vasodilatação/efeitos dos fármacos
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