RESUMO
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.
Assuntos
Aminoquinolinas/química , Benzamidas/química , Carbamatos/metabolismo , Proteínas de Transporte/antagonistas & inibidores , Indóis/metabolismo , Aminoquinolinas/síntese química , Aminoquinolinas/farmacocinética , Animais , Benzamidas/síntese química , Benzamidas/farmacocinética , Carbamatos/síntese química , Carbamatos/farmacocinética , Proteínas de Transporte/metabolismo , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Indóis/síntese química , Indóis/farmacocinética , Microssomos Hepáticos/metabolismo , Ratos , Triglicerídeos/metabolismoRESUMO
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.
Assuntos
Carbamatos/síntese química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/síntese química , Proteínas de Transporte/antagonistas & inibidores , Química Farmacêutica/métodos , Indóis/síntese química , Obesidade/tratamento farmacológico , Animais , Carbamatos/química , Carbamatos/farmacologia , Ácidos Carboxílicos/farmacologia , Cães , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Indóis/química , Indóis/farmacologia , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , RatosRESUMO
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.
Assuntos
Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Proteínas de Transporte/antagonistas & inibidores , Administração Oral , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/química , Proteínas de Transporte/metabolismo , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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.