Potent, orally bioavailable, liver-selective stearoyl-CoA desaturase (SCD) inhibitors

  • Bioorg Med Chem Lett. 2009 Aug 1;19(15):4070-4. doi: 10.1016/j.bmcl.2009.06.017.
Dmitry O Koltun  1 ,  Timur M Zilbershtein ,  Vasily A Migulin ,  Natalya I Vasilevich ,  Eric Q Parkhill ,  Andrei I Glushkov ,  Malcolm J McGregor ,  Sandra A Brunn ,  Nancy Chu ,  Jia Hao ,  Nevena Mollova ,  Kwan Leung ,  Jeffrey W Chisholm ,  Jeff Zablocki
Affiliations
  • 1. Department of Medicinal Chemistry, Gilead Sciences, Inc., 3172 Porter Dr., Palo Alto, CA 94304, USA. [email protected]
PMID: 19577469 DOI: 10.1016/j.bmcl.2009.06.017
Abstract

Two structurally distinct series of SCD (Delta9 desaturase) inhibitors (1 and 2) have been previously reported by our group. In the present work, we merged the structural features of the two series. This led to the discovery of compound 5b (CVT-12,012) which is highly potent in a human cell-based (HEPG2) SCD assay (IC(50)=6nM). This compound has 78% oral bioavailability in rats and is preferentially distributed into liver (76 times vs plasma) with relatively low brain penetration. In a five-day study (sucrose fed rats) compound 5b significantly reduced SCD activity in a dose-dependent manner as determined by GC analysis of fatty acid composition in plasma and liver, and significantly reduced liver triglycerides versus the control group ( approximately 50%).

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