Discovery of microsomal triglyceride transfer protein (MTP) inhibitors with potential for decreased active metabolite load compared to dirlotapide.

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.

In vitro and in vivo profile of 5-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid benzylmethyl carbamoylamide (dirlotapide), a novel potent MTP inhibitor for obesity.

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.

Discovery of potent and orally active MTP inhibitors as potential anti-obesity agents.

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.

Azalide 3,6-ketals: antibacterial activity and structure-activity relationships of aryl and hetero aryl substituted analogues.

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.