Small-sized human immunodeficiency virus type-1 protease inhibitors containing allophenylnorstatine to explore the S2' pocket

J Med Chem. 2009 Dec 10;52(23):7604-17. doi: 10.1021/jm9005115.

Abstract

A series of HIV protease inhibitor based on the allophenylnorstatine structure with various P(2)' moieties were synthesized. Among these analogues, we discovered that a small allyl group would maintain potent enzyme inhibitory activity compared to the o-methylbenzyl moiety in clinical candidate 1 (KNI-764, also known as JE-2147, AG-1776, or SM-319777). Introduction of an anilinic amino group to 2 (KNI-727) improved water-solubility and anti-HIV-1 activity. X-ray crystallographic analysis of 13k (KNI-1689) with a beta-methallyl group at P(2)' position revealed hydrophobic interactions with Ala28, Ile84, and Ile50' similar to that of 1. The presence of an additional methyl group on the allyl group in compound 13k significantly increased anti-HIV activity over 1 while providing a rational drug design for structural minimization and improving membrane permeability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • HIV Protease / chemistry*
  • HIV Protease / metabolism
  • HIV Protease Inhibitors / chemical synthesis
  • HIV Protease Inhibitors / chemistry*
  • HIV Protease Inhibitors / pharmacology*
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Phenylbutyrates / chemical synthesis
  • Phenylbutyrates / chemistry*
  • Phenylbutyrates / pharmacology*
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • HIV Protease Inhibitors
  • Phenylbutyrates
  • 3-amino-2-hydroxy-4-phenylbutanoic acid
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1