Spirodiketopiperazine-based CCR5 antagonists: Lead optimization from biologically active metabolite

Bioorg Med Chem Lett. 2007 Feb 1;17(3):727-31. doi: 10.1016/j.bmcl.2006.10.084. Epub 2006 Nov 1.

Abstract

Hydroxylated derivatives were designed and synthesized based on the information of oxidative metabolites. Compounds derived from beta-substituted (2R,3R)-2-amino-3-hydroxypropionic acid showed improved inhibitory activities against the binding of MIP-1alpha to human CCR5, compared with the non-hydroxylated derivatives and the other isomers.

MeSH terms

  • Animals
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / pharmacology*
  • CCR5 Receptor Antagonists*
  • CHO Cells
  • Chemokine CCL3
  • Chemokine CCL4
  • Chromatography, High Pressure Liquid
  • Combinatorial Chemistry Techniques
  • Cricetinae
  • Cricetulus
  • Drug Design
  • Humans
  • Hydroxylation
  • In Vitro Techniques
  • Indicators and Reagents
  • Isomerism
  • Macrophage Inflammatory Proteins / metabolism
  • Magnetic Resonance Spectroscopy
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism
  • Oxidation-Reduction
  • Protein Binding
  • Rats

Substances

  • Anti-HIV Agents
  • CCR5 Receptor Antagonists
  • Chemokine CCL3
  • Chemokine CCL4
  • Indicators and Reagents
  • Macrophage Inflammatory Proteins