RESUMO
A series of inhibitors of mammalian 15-lipoxygenase (15-LO) based on a 3,4,5-tri-substituted pyrazole scaffold is described. Replacement of a sulfonamide functionality in the lead series with a sulfamide group resulted in improved physicochemical properties generating analogs with enhanced inhibition in cell-based and whole blood assays.
Assuntos
Amidas/química , Araquidonato 15-Lipoxigenase/química , Inibidores de Lipoxigenase/química , Pirazóis/química , Amidas/síntese química , Amidas/farmacologia , Animais , Araquidonato 15-Lipoxigenase/metabolismo , Células CHO , Cricetinae , Cricetulus , Humanos , Ácidos Hidroxieicosatetraenoicos/sangue , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/farmacologia , Coelhos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
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/toxicidadeRESUMO
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-DawleyRESUMO
A series of 2,4,5-tri-substituted imidazoles has proven to be highly potent in inhibiting mammalian 15-lipoxygenase (15-LO) with excellent selectivity over human isozymes 5- and P-12-LO. Non-symmetrical sulfamides (e.g., 21a-n) were found to be suitable replacements for the earlier arylsulfonamide-containing members of this series (e.g., 2, 14a-p). Several members of these series also demonstrated potent inhibition of human 15-LO in a cell-based assay.
Assuntos
Imidazóis/farmacologia , Inibidores de Lipoxigenase , Inibidores de Lipoxigenase/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Imidazóis/química , Inibidores de Lipoxigenase/química , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
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 , EstereoisomerismoRESUMO
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/químicaRESUMO
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-AtividadeRESUMO
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.