2. Academic Validation
  3. Discovery of PF-04620110, a Potent, Selective, and Orally Bioavailable Inhibitor of DGAT-1

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

Affiliation

  • 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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