RESUMO
Alterations in fat metabolism, in particular elevated plasma concentrations of free fatty acids and triglycerides (TG), have been implicated in the pathogenesis of Type 2 diabetes, obesity, and cardiovascular disease. Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a member of the large family of membrane-bound O-acyltransferases, catalyzes the final step in triacylglycerol formation. In the intestine, DGAT1 is one of the acyltransferases responsible for the reesterficiation of dietary TG. Following a single dose of a selective pharmacological inhibitor of DGAT1, PF-04620110, a dose-dependent inhibition of TG and vitamin A absorption postprandially was demonstrated in rodents and human subjects. In C57/BL6J mice, acute DGAT1 inhibition alters the temporal and spatial pattern of dietary lipid absorption. To understand the impact of DGAT1 inhibition on enterocyte lipid metabolism, lipomic profiling was performed in rat intestine and plasma as well as human plasma. DGAT1 inhibition causes an enrichment of polyunsaturated fatty acids within the TG class of lipids. This pharmacological intervention gives us insight as to the role of DGAT1 in human dietary lipid absorption.
Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Absorção Intestinal/efeitos dos fármacos , Oxazepinas/farmacologia , Adolescente , Adulto , Animais , Estudos de Casos e Controles , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Gorduras na Dieta/sangue , Gorduras na Dieta/metabolismo , Relação Dose-Resposta a Droga , Enterócitos/metabolismo , Inibidores Enzimáticos/farmacocinética , Ácidos Graxos Insaturados/sangue , Ácidos Graxos Insaturados/metabolismo , Feminino , Humanos , Mucosa Intestinal/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Oxazepinas/farmacocinética , Período Pós-Prandial , Ratos , Ratos Sprague-Dawley , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Vitamina A/metabolismoRESUMO
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.