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. Epub 2010 Jan 21.

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.

MeSH terms

  • Animals
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacokinetics
  • Binding Sites
  • Crystallography, X-Ray
  • Dogs
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / metabolism
  • Heterocyclic Compounds / chemistry*
  • Humans
  • Hydrogen Bonding
  • Microsomes / metabolism
  • Mutant Proteins / antagonists & inhibitors
  • Mutant Proteins / metabolism
  • Pyrimidinones / chemical synthesis
  • Pyrimidinones / chemistry*
  • Pyrimidinones / pharmacokinetics
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacokinetics
  • Structure-Activity Relationship
  • Thymine / analogs & derivatives*
  • Thymine / chemical synthesis
  • Thymine / chemistry
  • Thymine / pharmacokinetics

Substances

  • Anti-HIV Agents
  • Heterocyclic Compounds
  • Mutant Proteins
  • Pyrimidinones
  • Reverse Transcriptase Inhibitors
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase
  • Thymine