Discovery of PF-04620110, a Potent, Selective, and Orally Bioavailable Inhibitor of DGAT-1

• DOI: 10.1021/ml200051p
• Publication Date: 2011-03-18T13:35:10Z
• Authors: Robert L. Dow; Jian-Cheng Li; Michael P. Pence; E. Michael Gibbs; Jennifer L. LaPerle; John Litchfield; David W. Piotrowski; Michael J. Munchhof; Tara B. Manion; William J. Zavadoski; Gregory S. Walker; R. Kirk McPherson; Susan Tapley; Eliot Sugarman; Angel Guzman-Perez; Paul DaSilva-Jardine
• Keywords: 0301 basic medicine; 03 medical and health sciences; 3. Good health

Acyl-CoA:diacylglycerol acyltransferase-1 (DGAT-1) catalyzes the final committed step in the biosynthesis of triglycerides. DGAT-1 knockout mice have been shown to be resistant to diet-induced obesity and have increased insulin sensitivity. Thus, inhibition of DGAT-1 may represent an attractive target for the treatment of obesity or type II diabetes. Herein, we report the discovery and characterization of a potent and selective DGAT-1 inhibitor PF-04620110 (3). Compound 3 inhibits DGAT-1 with an IC50 of 19 nM and shows high selectivity versus a broad panel of off-target pharmacologic end points. In vivo DGAT-1 inhibition has been demonstrated through reduction of plasma triglyceride levels in rodents at doses of ≥0.1 mg/kg following a lipid challenge. On the basis of this pharmacologic and pharmacokinetic profile, compound 3 has been advanced to human clinical studies.