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
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
Recent literature has suggested the benefit of selective PPARdelta agonists for the treatment of atherosclerosis and other disease states associated with the metabolic syndrome. Herein we report the synthesis and structure-activity relationships of a series of novel and selective PPARdelta agonists. Our search began with identification of a novel benzothiophene template which was modified by the addition of various thiazolyl, isoxazolyl, and benzyloxy-benzyl moieties. Further elucidation of the SAR led to the identification of benzofuran and indole based templates. During the course of our research, we discovered three new chemical templates with varying degrees of affinity and potency for PPARdelta versus the PPARalpha and PPARgamma subtypes.
Asunto(s)
Benzofuranos/química , Química Farmacéutica/métodos , Indoles/química , PPAR delta/agonistas , Tiofenos/química , Animales , Benzofuranos/síntesis química , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Indoles/síntesis química , Concentración 50 Inhibidora , Ligandos , Modelos Químicos , Relación Estructura-Actividad , Tiazoles/química , Tiofenos/síntesis químicaRESUMEN
A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's < or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.
