Discovery and optimization of 2-phenyloxazole derivatives as diacylglycerol acyltransferase-1 inhibitors

  • Bioorg Med Chem Lett. 2011 Dec 1;21(23):7205-9. doi: 10.1016/j.bmcl.2011.09.039.
Weiya Yun  1 ,  Mushtaq Ahmad ,  Yingsi Chen ,  Paul Gillespie ,  Karin Conde-Knape ,  Sonja Kazmer ,  Shiming Li ,  Yimin Qian ,  Rebecca Taub ,  Stanley J Wertheimer ,  Toni Whittard ,  David Bolin
Affiliations
  • 1. Roche Research Center, Hoffmann-La Roche, Inc., Nutley, NJ 07110, USA. [email protected]
PMID: 22001092 DOI: 10.1016/j.bmcl.2011.09.039
Abstract

In a discovery effort to find safe and effective DGAT-1 inhibitors, we have identified 2-phenyloxazole 4-carboxamide 1 as a conformationally constrained analog of a hydrazide hit, which was previously identified from high-throughput screening. Further optimization of this series has led to chemically more stable 2-phenyloxazole-based DGAT-1 inhibitor 25 with improved solubility, cell-based activity, and pharmacokinetic properties. Compound 25 also demonstrated in vivo efficacy in a diet-induced obesity (DIO) rat model.