Design and synthesis of potent, orally-active DGAT-1 inhibitors containing a dioxino[2,3-d]pyrimidine core PMID: 21908190

ADC Targets in Oncology

2026-04-10

Design and synthesis of potent, orally-active DGAT-1 inhibitors containing a dioxino[2,3-d]pyrimidine core

Bioorg Med Chem Lett. 2011 Oct 15;21(20):6122-5. doi: 10.1016/j.bmcl.2011.08.028.

Robert L Dow ¹ , Melissa Andrews , Gary E Aspnes , Gayatri Balan , E Michael Gibbs , Angel Guzman-Perez , Kapil Karki , Jennifer L Laperle , Jian-Cheng Li , John Litchfield , Michael J Munchhof , Christian Perreault , Leena Patel

Affiliations

Abstract

A novel series of potent DGAT-1 inhibitors was developed originating from the lactam-based clinical candidate PF-04620110. Incorporation of a dioxino[2,3-d]pyrimidine-based core afforded good alignment of pharmacophore features and resulted in improved passive permeability. Development of an efficient, homochiral synthesis of these targets facilitated confirmation of predictions regarding the stereochemical-dependence of DGAT-1 inhibition for this series. Compound 10 was shown to be a potent inhibitor of human DGAT-1 (10 nM) and to suppress triglyceride synthesis at oral doses of <3mg/kg.