Discovery of 4-[4-({(3R)-1-butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenoxy]benzoic acid hydrochloride: a highly potent orally available CCR5 selective antagonist

Bioorg Med Chem. 2011 Jul 1;19(13):4028-42. doi: 10.1016/j.bmc.2011.05.022. Epub 2011 May 20.

Abstract

Based on the original spirodiketopiperazine design framework, further optimization of an orally available CCR5 antagonist was undertaken. Structural hybridization of the hydroxylated analog 4 derived from one of the oxidative metabolites and the new orally available non-hydroxylated benzoic acid analog 5 resulted in another potent orally available CCR5 antagonist 6a as a clinical candidate. Full details of a structure-activity relationship (SAR) study and ADME properties are presented.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacokinetics
  • Benzoates / chemical synthesis
  • Benzoates / chemistry*
  • Benzoates / pharmacokinetics
  • CCR5 Receptor Antagonists*
  • Diketopiperazines / chemical synthesis
  • Diketopiperazines / chemistry*
  • Diketopiperazines / pharmacokinetics
  • Dogs
  • Drug Evaluation, Preclinical
  • Guinea Pigs
  • Haplorhini
  • Humans
  • Rabbits
  • Rats
  • Receptors, CCR5 / metabolism
  • Structure-Activity Relationship

Substances

  • 4-(4-((1-butyl-3-(cyclohexyl(hydroxy)methyl)-2,5-dioxo-1,4,9-triazaspiro(5.5)undec-9-yl)methyl)phenoxy)benzoic acid
  • Anti-HIV Agents
  • Benzoates
  • CCR5 Receptor Antagonists
  • Diketopiperazines
  • Receptors, CCR5