Novel 1,5-diphenylpyrazole nonnucleoside HIV-1 reverse transcriptase inhibitors with enhanced activity versus the delavirdine-resistant P236L mutant: lead identification and SAR of 3- and 4-substituted derivatives

J Med Chem. 2000 Mar 9;43(5):1034-40. doi: 10.1021/jm990383f.

Abstract

Through computationally directed broad screening, a novel 1, 5-diphenylpyrazole (DPP) class of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been discovered. Compound 2 (PNU-32945) was found to have good activity versus wild-type (IC(50) = 2.3 microM) and delavirdine-resistant P236L (IC(50) = 1.1 microM) reverse transcriptase (RT). Also, PNU-32945 has an ED(50) for inhibition of viral replication in cell cultures of 0.1 microM and was shown to be noncytotoxic with a CC(50) > 10 microM. Structure-activity relationship studies on the 3- and 4-positions of PNU-32945 led to interesting selectivity and activity within the class. In particular, the 3-hydroxyethyl-4-ethyl congener 29 is a potent inhibitor of the P236L mutant (IC(50) = 0.65 microM), whereas it is essentially inactive versus the wild-type enzyme (IC(50) > 50 microM). Furthermore, this compound was significantly more active versus the P236L mutant than delavirdine. The synthesis and RT inhibitory activity of various 3- and 4-substituted analogues are discussed.

MeSH terms

  • Anti-HIV Agents / pharmacology*
  • Delavirdine / pharmacology*
  • Drug Resistance, Microbial
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / genetics
  • Mutation
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • 1,5-diphenyl-3-(2-hydroxyethyl)-4-ethylpyrazole
  • Anti-HIV Agents
  • Pyrazoles
  • Reverse Transcriptase Inhibitors
  • Delavirdine
  • HIV Reverse Transcriptase