RESUMEN
The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (26) as a candidate for treating hypercholesterlemia. Clinical evaluation of 26 (PF-03491165), as well as the previously reported 2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors.
Asunto(s)
Descubrimiento de Drogas , Ácidos Heptanoicos/síntesis química , Inhibidores de Hidroximetilglutaril-CoA Reductasas/síntesis química , Hipercolesterolemia/tratamiento farmacológico , Imidazoles/síntesis química , Hígado/efectos de los fármacos , Animales , Células Cultivadas , Perros , Relación Dosis-Respuesta a Droga , Hepatocitos/efectos de los fármacos , Ácidos Heptanoicos/química , Ácidos Heptanoicos/farmacocinética , Ácidos Heptanoicos/farmacología , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Imidazoles/química , Imidazoles/farmacocinética , Imidazoles/farmacología , Concentración 50 Inhibidora , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacocinética , Pirazoles/farmacología , Ratas , Distribución TisularRESUMEN
4-Sulfamoyl pyrroles were designed as novel hepatoselective HMG-CoA reductase inhibitors (statins) to reduce myalgia, a statin-induced adverse effect. The compounds were prepared via a [3+2] cycloaddition of a Münchnone with a sulfonamide-substituted alkyne. We identified compounds with greater selectivity for hepatocytes compared to L6-myocytes than rosuvastatin and atorvastatin. There was an inverse correlation of myocyte potencies and ClogP values. A number of analogs were effective at reducing cholesterol in acute and chronic in vivo models but they lacked sufficient chronic in vivo activity to warrant further development.
Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/síntesis química , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Células Musculares/efectos de los fármacos , Pirroles/síntesis química , Pirroles/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Animales , Atorvastatina , Técnicas Químicas Combinatorias , Modelos Animales de Enfermedad , Fluorobencenos/farmacología , Hepatocitos/efectos de los fármacos , Ácidos Heptanoicos/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/química , Ratones , Estructura Molecular , Pirimidinas/farmacología , Pirroles/química , Rosuvastatina CálcicaRESUMEN
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
Using structure-based design, a novel series of conformationally restricted, pyrrole-based inhibitors of HMG-CoA reductase were discovered. Leading analogs demonstrated potent inhibition of cholesterol synthesis in both in vitro and in vivo models and may be useful for the treatment of hypercholesterolemia and related lipid disorders.
Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/síntesis química , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Pirroles/química , Pirroles/farmacología , Animales , Colesterol/biosíntesis , Diseño de Fármacos , Hiperlipidemias/tratamiento farmacológico , Ratones , Biología Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/química , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Pirroles/química , Pirroles/farmacología , Animales , Cricetinae , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Fluorobencenos , Hiperlipidemias/tratamiento farmacológico , Hígado/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Pirimidinas , Rosuvastatina Cálcica , Relación Estructura-Actividad , SulfonamidasRESUMEN
Interleukin-8 modulation is implicated in many inflammatory and cancer diseases. Starting from a mass-screening hit, the synthesis and structure-activity relationship of 2-amino-3-heteroarylquinoxalines as non-peptide, small molecule interleukine-8 receptor antagonists have been developed. The optimized derivatives, PD 0210293 (13y) and PD 0220245 (13r), show inhibition of both IL-8 receptor binding and IL-8-mediated neutrophil chemotaxis.