RESUMEN
A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFß receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFß induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.
Asunto(s)
Cicatriz/prevención & control , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piridinas/química , Piridinas/farmacología , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Piel/efectos de los fármacos , Animales , Modelos Moleculares , Fosforilación , Ratas , Receptor Tipo I de Factor de Crecimiento Transformador betaRESUMEN
Clinical studies have demonstrated that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) inhibitors, are effective at lowering mortality levels associated with cardiovascular disease; however, 2-7% of patients may experience statin-induced myalgia that limits compliance with a treatment regimen. High resolution crystal structures, thermodynamic binding parameters, and biochemical data were used to design statin inhibitors with improved HMGR affinity and therapeutic index relative to statin-induced myalgia. These studies facilitated the identification of imidazole 1 as a potent (IC 50 = 7.9 nM) inhibitor with excellent hepatoselectivity (>1000-fold) and good in vivo efficacy. The binding of 1 to HMGR was found to be enthalpically driven with a Delta H of -17.7 kcal/M. Additionally, a second novel series of bicyclic pyrrole-based inhibitors was identified that induced order in a protein flap of HMGR. Similar ordering was detected in a substrate complex, but has not been reported in previous statin inhibitor complexes with HMGR.
Asunto(s)
Diseño de Fármacos , Hidroximetilglutaril-CoA Reductasas/química , Hidroximetilglutaril-CoA Reductasas/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/química , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Termodinámica , Animales , Sitios de Unión , Calorimetría , Células Cultivadas , Cristalografía por Rayos X , Fluorobencenos/química , Fluorobencenos/farmacología , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Imidazoles/química , Imidazoles/farmacología , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Modelos Moleculares , Estructura Molecular , Células Musculares/efectos de los fármacos , Células Musculares/enzimología , Pirimidinas/química , Pirimidinas/farmacología , Pirroles/química , Pirroles/farmacología , Ratas , Rosuvastatina Cálcica , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
A series of 1,4-benzyloxybenzylsulfanylaryl carboxylic acids were prepared and their activities for PPAR receptor subtypes (alpha, delta, and gamma) with potential indications for the treatment of dyslipidemia were investigated. Analog 13a displayed the greatest binding affinity (IC(50)=10nM) and selectivity (120-fold) for PPARdelta over PPARalpha. Many of the analogs investigated were found to be highly selective for PPARdelta and were dependent on the point of attachment of the substituent. In the 1,4-series, analog 28e was found to be the most potent (IC(50)=1.7 nM) and selective (>1000-fold) compound for PPARdelta. None of the compounds tested showed appreciable binding affinity for PPARgamma.
Asunto(s)
Ácidos Carboxílicos/química , Química Farmacéutica/métodos , PPAR delta/agonistas , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ligandos , Lípidos/química , Modelos Químicos , PPAR delta/química , Unión Proteica , Relación Estructura-Actividad , Compuestos de Sulfhidrilo/química , TemperaturaRESUMEN
In an effort to identify hepatoselective inhibitors of HMG-CoA reductase, two series of pyrroles were synthesized and evaluated. Efforts were made to modify (3R,5R)-7-[3-(4-fluorophenyl)-1-isopropyl-4-phenyl-5-phenylcarbamoyl-1H-pyrrol-2-yl]-3,5-dihydroxy-heptanoic acid sodium salt 30 in order to reduce its lipophilicity and therefore increase hepatoselectivity. Two strategies that were explored were replacement of the lipophilic 3-phenyl substituent with either a polar function (pyridyl series) or with lower alkyl substituents (lower alkyl series) and attachment of additional polar moieties at the 2-position of the pyrrole ring. One compound was identified to be both highly hepatoselective and active in vivo. We report the discovery, synthesis, and optimization of substituted pyrrole-based hepatoselective ligands as potent inhibitors of HMG-CoA reductase for reducing low density lipoprotein cholesterol (LDL-c) in the treatment of hypercholesterolemia.
Asunto(s)
Hidroximetilglutaril-CoA Reductasas/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/síntesis química , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hígado/efectos de los fármacos , Hígado/enzimología , Pirroles/química , Pirroles/farmacología , Animales , Colesterol/biosíntesis , Inhibidores de Hidroximetilglutaril-CoA Reductasas/química , Ligandos , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Estructura Molecular , Pirroles/síntesis química , Ratas , Ratas Sprague-DawleyRESUMEN
This manuscript describes the design and synthesis of a series of pyrrole-based inhibitors of HMG-CoA reductase for the treatment of hypercholesterolemia. Analogs were optimized using structure-based design and physical property considerations resulting in the identification of 44, a hepatoselective HMG-CoA reductase inhibitor with excellent acute and chronic efficacy in a pre-clinical animal models.