pf-04620110 and Obesity

A series of benzimidazole derivatives with a phenylcyclohexyl acetic acid group as DGAT-1 inhibitors was developed. Among the benzimidazole series, compound 5k showed submicromolar in vitro activity toward human and mouse DGAT-1, good selectivity toward DGAT-2, human liver metabolic stability, and pharmacokinetic (PK) and safety profiles such as hERG, CYP and acute toxicity. Additionally, 5k showed good in vivo efficacy in 4weeks study with DIO mouse model.

Topics: Acetic Acid; Animals; Anti-Obesity Agents; Benzimidazoles; Cells, Cultured; Cyclization; Diabetes Mellitus; Disease Models, Animal; Humans; Hypoglycemic Agents; Liver; Mice; Molecular Structure; Obesity

DGAT-1 is an enzyme that catalyzes the final step in triglyceride synthesis. mRNA knockout experiments in rodent models suggest that inhibitors of this enzyme could be of value in the treatment of obesity and type II diabetes. The carboxylic acid-based DGAT-1 inhibitor 1 was advanced to clinical trials for the treatment of type 2 diabetes, despite of the low passive permeability of 1. Because of questions relating to the potential attenuation of distribution and efficacy of a poorly permeable agent, efforts were initiated to identify compounds with improved permeability. Replacement of the acid moiety in 1 with an oxadiazole led to the discovery of 52, which possesses substantially improved passive permeability. The resulting pharmacodynamic profile of this neutral DGAT-1 inhibitor was found to be similar to 1 at comparable plasma exposures.

Topics: Administration, Oral; Animals; Diacylglycerol O-Acyltransferase; Drug Evaluation, Preclinical; Enzyme Inhibitors; Half-Life; Humans; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Oxadiazoles; Oxazepines; Protein Binding; Rats; Structure-Activity Relationship