Aminodiol HIV protease inhibitors. Synthesis and structure-activity relationships of P1/P1' compounds: correlation between lipophilicity and cytotoxicity

  • J Med Chem. 1996 May 10;39(10):1991-2007. doi: 10.1021/jm950717a.
P Chen  1 ,  P T Cheng ,  M Alam ,  B D Beyer ,  G S Bisacchi ,  T Dejneka ,  A J Evans ,  J A Greytok ,  M A Hermsmeier ,  W G Humphreys ,  G A Jacobs ,  O Kocy ,  P F Lin ,  K A Lis ,  M A Marella ,  D E Ryono ,  A K Sheaffer ,  S H Spergel ,  C Q Sun ,  J A Tino ,  G Vite ,  R J Colonno ,  R Zahler ,  J C Barrish
Affiliations
  • 1. Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
PMID: 8642558 DOI: 10.1021/jm950717a
Abstract

A series of novel aminodiol inhibitors of HIV Protease based on the lead compound 1 with structural modifications at P1' were synthesized in order to reduce the cytotoxicity of 1. We have observed a high degree of correlation between the lipophilicity and cytotoxicity of this series of inhibitors. It was found that appropriate substitution at the para position of the P1' phenyl group of 1 resulted in the identification of equipotent (both against the enzyme and in Cell Culture) compounds (10l, 10m, 10n, and 15c) which possess significantly decreased cytotoxicity.