ABSTRACT
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.
Subject(s)
Aminoquinolines/chemistry , Benzamides/chemistry , Carbamates/metabolism , Carrier Proteins/antagonists & inhibitors , Indoles/metabolism , Aminoquinolines/chemical synthesis , Aminoquinolines/pharmacokinetics , Animals , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , Carbamates/chemical synthesis , Carbamates/pharmacokinetics , Carrier Proteins/metabolism , Dogs , Drug Evaluation, Preclinical , Humans , Indoles/chemical synthesis , Indoles/pharmacokinetics , Microsomes, Liver/metabolism , Rats , Triglycerides/metabolismABSTRACT
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.