1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 4: synthesis of N-1 acidic functionality affording analogues with enhanced antiviral activity against HIV

Christopher L Lynch; Jeffrey J Hale; Richard J Budhu; Amy L Gentry; Sander G Mills; Kevin T Chapman; Malcolm MacCoss; Lorraine Malkowitz; Martin S Springer; Sandra L Gould; Julie A DeMartino; Salvatore J Siciliano; Margaret A Cascieri; Anthony Carella; Gwen Carver; Karen Holmes; William A Schleif; Renee Danzeisen; Daria Hazuda; Joseph Kessler; Janet Lineberger; Michael Miller; Emilio A Emini

doi:10.1016/s0960-894x(02)00606-6

1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 4: synthesis of N-1 acidic functionality affording analogues with enhanced antiviral activity against HIV

Bioorg Med Chem Lett. 2002 Oct 21;12(20):3001-4. doi: 10.1016/s0960-894x(02)00606-6.

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. chris_lynch@merck.com

PMID: 12270193
DOI: 10.1016/s0960-894x(02)00606-6

Abstract

A series of alpha-(pyrrolidin-1-yl)acetic acids is presented as selective and potent antivirals against HIV. Several of the pyrrolidine zwitterions demonstrated reasonable in vitro properties, enhanced antiviral activities and improved pharmacokinetic profiles over pyrrolidine 1.

MeSH terms

Animals
Anti-HIV Agents / chemical synthesis*
Anti-HIV Agents / pharmacokinetics
Anti-HIV Agents / pharmacology*
CCR5 Receptor Antagonists*
CHO Cells
Cell Membrane Permeability
Chemical Phenomena
Chemistry, Physical
Chemokine CCL4
Cricetinae
HIV-1 / drug effects*
HeLa Cells
Humans
Indicators and Reagents
Macrophage Inflammatory Proteins / antagonists & inhibitors
Pyrrolidines / chemical synthesis*
Pyrrolidines / pharmacokinetics
Pyrrolidines / pharmacology*
Rats
Structure-Activity Relationship

Substances

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