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

  • ACS Med Chem Lett. 2011 Mar 18;2(5):407-12. doi: 10.1021/ml200051p.
Robert L Dow  1 ,  Jian-Cheng Li  1 ,  Michael P Pence  1 ,  E Michael Gibbs  1 ,  Jennifer L LaPerle  1 ,  John Litchfield  1 ,  David W Piotrowski  1 ,  Michael J Munchhof  1 ,  Tara B Manion  1 ,  William J Zavadoski  1 ,  Gregory S Walker  1 ,  R Kirk McPherson  1 ,  Susan Tapley  1 ,  Eliot Sugarman  1 ,  Angel Guzman-Perez  1 ,  Paul DaSilva-Jardine  1
Affiliations
  • 1. Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
PMID: 24900321 DOI: 10.1021/ml200051p
Abstract

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.

Keywords
DGAT-1; acyl glucuronide; diabetes; obesity; phototoxicity; triglyceride.
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