Synthesis and biological evaluation of 1,3,3,4-tetrasubstituted pyrrolidine CCR5 receptor antagonists. Discovery of a potent and orally bioavailable anti-HIV agent

ChemMedChem. 2007 Feb;2(2):187-93. doi: 10.1002/cmdc.200600182.


A series of 1,3,3,4-tetrasubstituted pyrrolidine containing CCR5 receptor antagonists were designed, which were elaborated either by condensation of a lithium salt of 3-(N,N-dibenzyl)aminopropionic acid methyl ester with ethyl benzoformate or by Baylis-Hillman reaction of ethyl acrylate with ethyl benzoformate and subsequent 1,4-addition of benzylamine, in the key steps. These compounds bearing 4-(N,N-disubstituted)amino piperidine units showed low nanomolar potency against the CCR5 receptor, whereas molecules with a 4-phenylpiperidine moiety displayed poor activity. Asymmetric synthesis of the most potent compound 23 a gave rise to the (3R,4S)-enantiomer 30 and the (3S,4R)-enantiomer 31, which showed IC(50) values of 2.9 and 385.9 nM, respectively. These results indicated that (3R,4S)-configuration in the series of compounds is favored for their interaction with the CCR5 receptor. The possible binding mode of these antagonists with the CCR5 receptor was discussed using a computer-modeling method. Compound 30 displayed excellent replication inhibition of seven genetically diverse R5 HIV-1 strains in the PBMC model, in a concentration-dependent manner with EC(50) values ranging from 0.3 nM to 30 nM. This molecule showed oral bioavailabilities of 41.2 % and 21.6 % in rats and dogs, respectively. Thus, compound 30 is a promising candidate for the treatment of HIV-1 infection.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-HIV Agents / administration & dosage*
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / pharmacokinetics
  • Biological Availability
  • CCR5 Receptor Antagonists*
  • Dogs
  • HIV Infections / metabolism
  • Models, Chemical
  • Pyrrolidines / administration & dosage
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / pharmacokinetics
  • Rats
  • Structure-Activity Relationship
  • Virus Replication / drug effects*
  • Virus Replication / physiology


  • Anti-HIV Agents
  • CCR5 Receptor Antagonists
  • Pyrrolidines