1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists: modifications of the arylpropylpiperidine side chains

Christopher L Lynch; Christopher A Willoughby; Jeffrey J Hale; Edward J Holson; Richard J Budhu; Amy L Gentry; Keith G Rosauer; Charles G Caldwell; Ping Chen; Sander G Mills; Malcolm MacCoss; Scott Berk; Liya Chen; Kevin T Chapman; 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)00829-6

1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists: modifications of the arylpropylpiperidine side chains

Bioorg Med Chem Lett. 2003 Jan 6;13(1):119-23. doi: 10.1016/s0960-894x(02)00829-6.

Affiliation

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

PMID: 12467630
DOI: 10.1016/s0960-894x(02)00829-6

Abstract

The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics.

MeSH terms

Animals
Anti-HIV Agents / chemical synthesis*
Anti-HIV Agents / pharmacokinetics
Anti-HIV Agents / pharmacology
CCR5 Receptor Antagonists*
Dogs
Half-Life
Humans
Leukocytes, Mononuclear
Macaca mulatta
Metabolic Clearance Rate
Piperidines / chemistry
Pyrrolidines / chemical synthesis
Pyrrolidines / pharmacokinetics*
Pyrrolidines / pharmacology
Radioligand Assay
Rats
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Anti-HIV Agents
CCR5 Receptor Antagonists
Piperidines
Pyrrolidines
piperidine