HIV protease inhibitors with picomolar potency against PI-Resistant HIV-1 by extension of the P3 substituent

Bioorg Med Chem Lett. 2003 Aug 4;13(15):2569-72. doi: 10.1016/s0960-894x(03)00475-x.

Abstract

A biaryl pyridylfuran P(3) substituent on the hydroxyethylene isostere scaffold affords HIV protease inhibitors (PI's) with picomolar (IC(50)) potency against the protease enzymes from PI-resistant HIV-1 strains. Inclusion of a gem-dimethyl substituent afforded compound 3 with 100% oral bioavailability (dogs) and more than double the t(1/2) of indinavir. Inhibition of multiple P450 isoforms is dependent on the regiochemistry of the pyridyl nitrogen in these compounds.

MeSH terms

  • Animals
  • Biological Availability
  • Cytochrome P-450 Enzyme Inhibitors
  • Dogs
  • Drug Resistance, Viral*
  • HIV Protease Inhibitors / chemical synthesis*
  • HIV Protease Inhibitors / pharmacokinetics
  • HIV Protease Inhibitors / pharmacology*
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • Half-Life
  • Indinavir / pharmacokinetics
  • Isoenzymes / antagonists & inhibitors
  • Macaca mulatta
  • Mutation / genetics
  • Structure-Activity Relationship

Substances

  • Cytochrome P-450 Enzyme Inhibitors
  • HIV Protease Inhibitors
  • Isoenzymes
  • Indinavir