title: Discovery of PF-04620110, a Potent, Selective, and Orally Bioavailable Inhibitor of DGAT-1.
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.
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Dow
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Jian-Cheng
authors.initials: JC
authors.lastname: Li
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Pence
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: E Michael
authors.initials: EM
authors.lastname: Gibbs
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: LaPerle
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: John
authors.initials: J
authors.lastname: Litchfield
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: David W
authors.initials: DW
authors.lastname: Piotrowski
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Munchhof
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Tara B
authors.initials: TB
authors.lastname: Manion
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Zavadoski
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Walker
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: R Kirk
authors.initials: RK
authors.lastname: McPherson
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Tapley
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Eliot
authors.initials: E
authors.lastname: Sugarman
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Angel
authors.initials: A
authors.lastname: Guzman-Perez
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: DaSilva-Jardine
keywords: DGAT-1; acyl glucuronide; diabetes; obesity; phototoxicity; triglyceride