N1-Heterocyclic pyrimidinediones as non-nucleoside inhibitors of HIV-1 reverse transcriptase

  • Bioorg Med Chem Lett. 2010 Mar 1;20(5):1585-8. doi: 10.1016/j.bmcl.2010.01.086.
Michael L Mitchell  1 ,  Jong Chan Son ,  Ill Young Lee ,  Chong-Kyo Lee ,  Hae Soo Kim ,  Hongyan Guo ,  Jianhong Wang ,  Jaclyn Hayes ,  Michael Wang ,  Amber Paul ,  Eric B Lansdon ,  James M Chen ,  Gene Eisenberg ,  Romas Geleziunas ,  Lianhong Xu ,  Choung U Kim
Affiliations
  • 1. Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. [email protected]
PMID: 20137928 DOI: 10.1016/j.bmcl.2010.01.086
Abstract

A series of N1-heterocyclic pyrimidinediones were extensively evaluated as HIV-1 non-nucleoside Reverse Transcriptase inhibitors (NNRTIs). Inhibitor 1 is active against NNRTI-resistant viruses including RT mutant K103N. The co-crystal structure of inhibitor 1 with HIV-1 RT revealed that H-bonds are formed with K101 and K103. Efforts to improve the suboptimal pharmacokinetic profile of 1 resulted in the discovery of compound 13, which represents the lead compound in this series with improved pharmacokinetics and similar potency as inhibitor 1.