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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

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, etc.

ACS Med Chem Lett. 2011 Mar 18;2(5):407-12.

PMID: 24900321

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1109276892	PF-04620110		1109276-89-2	Price

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