ABSTRACT
Modification of a gut restricted class of benzimidazole DGAT1 inhibitor 1 led to 9 with good oral bioavailability. The key structural changes to 1 include bioisosteric replacement of the amide with oxadiazole and α,α-dimethylation of the carboxylic acid, improving DGAT1 potency and gut permeability. Since DGAT1 is expressed in the small intestine, both 1 and 9 can suppress postprandial triglycerides during acute oral lipid challenges in rats and dogs. Interestingly, only 9 was found to be effective in suppressing body weight gain relative to control in a diet-induced obese dog model, suggesting the importance of systemic inhibition of DGAT1 for body weight control. 9 has advanced to clinical investigation and successfully suppressed postprandial triglycerides during an acute meal challenge in humans.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Diet, High-Fat , Enzyme Inhibitors/pharmacology , Obesity/physiopathology , Triglycerides/blood , Weight Gain/drug effects , Administration, Oral , Adolescent , Adult , Animals , Dogs , Double-Blind Method , Drug Discovery , Enzyme Inhibitors/administration & dosage , Female , Humans , Male , Middle Aged , Placebos , Postprandial Period , Rats , Rats, Sprague-Dawley , Young AdultABSTRACT
Diamide compounds were identified as potent DGAT1 inhibitors in vitro, but their poor molecular properties resulted in low oral bioavailability, both systemically and to DGAT1 in the enterocytes of the small intestine, resulting in a lack of efficacy in vivo. Replacing an N-alkyl group on the diamide with an N-aryl group was found to be an effective strategy to confer oral bioavailability and oral efficacy in this lipophilic diamide class of inhibitors.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Diamide/chemistry , Enzyme Inhibitors/chemistry , Animals , Cell Line, Tumor , Diacylglycerol O-Acyltransferase/metabolism , Diamide/chemical synthesis , Diamide/pharmacokinetics , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Half-Life , Humans , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A series of 2-[(2,6)-dimethylphenyl]benzimidazole analogs displayed strong potential for mutagenicity following metabolic activation in either TA98 or TA100 Salmonella typhimurium strains. The number of revertants was significantly reduced by replacing the 2,6-dimethylphenyl group with a 2,6-dichlorophenyl moiety. Time-dependent CYP3A4 inhibition was also observed with a compound containing a 2-[(2,6)-dimethylphenyl] benzimidazole ring, implying risk for this scaffold to generate reactive metabolites.
