RESUMEN
Analogues related to dirlotapide (1), a gut-selective inhibitor of microsomal triglyceride transfer protein (MTP) were prepared with the goal of further reducing the potential for unwanted liver MTP inhibition and associated side-effects. Compounds were designed to decrease active metabolite load: reducing MTP activity of likely human metabolites and increasing metabolite clearance to reduce exposure. Introduction of 4'-alkyl and 4'-alkoxy substituents afforded compounds exhibiting improved therapeutic index in rats with respect to liver triglyceride accumulation and enzyme elevation. Likely human metabolites of select compounds were prepared and characterized for their potential to inhibit MTP in vivo. Based on preclinical efficacy and safety data and its potential for producing short-lived, weakly active metabolites, compound 13 (PF-02575799) advanced into phase 1 clinical studies.
Asunto(s)
Aminoquinolinas/química , Benzamidas/química , Carbamatos/metabolismo , Proteínas Portadoras/antagonistas & inhibidores , Indoles/metabolismo , Aminoquinolinas/síntesis química , Aminoquinolinas/farmacocinética , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Carbamatos/síntesis química , Carbamatos/farmacocinética , Proteínas Portadoras/metabolismo , Perros , Evaluación Preclínica de Medicamentos , Humanos , Indoles/síntesis química , Indoles/farmacocinética , Microsomas Hepáticos/metabolismo , Ratas , Triglicéridos/metabolismoRESUMEN
The synthesis of a novel gut selective MTP inhibitor, 5-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid benzylmethyl carbamoylamide (dirlotapide), and its in vitro and in vivo profile are described. Dirlotapide (3) demonstrated excellent potency against MTP enzyme in HepG2 cells and canine hepatocytes. This novel MTP inhibitor also showed excellent efficacy when tested in a canine food intake model.
Asunto(s)
Carbamatos/síntesis química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/síntesis química , Proteínas Portadoras/antagonistas & inhibidores , Química Farmacéutica/métodos , Indoles/síntesis química , Obesidad/tratamiento farmacológico , Animales , Carbamatos/química , Carbamatos/farmacología , Ácidos Carboxílicos/farmacología , Perros , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Concentración de Iones de Hidrógeno , Técnicas In Vitro , Indoles/química , Indoles/farmacología , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , RatasRESUMEN
We have successfully identified a number of novel MTP inhibitors with single digit nanomolar potency. Analogues 10aq and 10dq demonstrated in vivo efficacy in a murine gut retention assay.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacología , Proteínas Portadoras/antagonistas & inhibidores , Administración Oral , Animales , Fármacos Antiobesidad/administración & dosificación , Fármacos Antiobesidad/química , Proteínas Portadoras/metabolismo , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Aryl and hetero aryl substituted 3,6-ketals of 15-membered azalide analogues were synthesized and were found to have potent in vitro antibacterial activity against veterinary pathogens, including Staphylococcus aureus and Pasteurella multocida.