Microwave-accelerated synthesis of P1'-extended HIV-1 protease inhibitors encompassing a tertiary alcohol in the transition-state mimicking scaffold

J Med Chem. 2006 Mar 9;49(5):1828-32. doi: 10.1021/jm051239z.

Abstract

Two series of P1'-extended HIV-1 protease inhibitors comprising a tertiary alcohol in the transition-state mimic exhibiting Ki values ranging from 2.1 to 93 nM have been synthesized. Microwave-accelerated palladium-catalyzed cross-couplings were utilized to rapidly optimize the P1' side chain. High cellular antiviral potencies were encountered when the P1' benzyl group was elongated with a 3- or 4-pyridyl substituent (EC50 = 0.18-0.22 microM). X-ray crystallographic data were obtained for three inhibitors cocrystallized with the enzyme.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohols / chemical synthesis*
  • Alcohols / chemistry
  • Alcohols / pharmacology
  • Binding Sites
  • Catalysis
  • Cell Line
  • Crystallography, X-Ray
  • HIV Protease / chemistry*
  • HIV Protease Inhibitors / chemical synthesis*
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / pharmacology
  • HIV-1 / drug effects
  • Humans
  • Hydrogen Bonding
  • Indans / chemical synthesis*
  • Indans / chemistry
  • Indans / pharmacology
  • Microwaves
  • Molecular Mimicry
  • Palladium

Substances

  • Alcohols
  • HIV Protease Inhibitors
  • Indans
  • Palladium
  • HIV Protease