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
PMID: 21908190 DOI: 10.1016/j.bmcl.2011.08.028
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.

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