2. Academic Validation
  3. N1-Heterocyclic pyrimidinediones as non-nucleoside inhibitors of HIV-1 reverse transcriptase

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

Affiliation

  • 1 Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. mmitchell@gilead.com
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.

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