1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 1: discovery of the pyrrolidine scaffold and determination of its stereochemical requirements

J J Hale; R J Budhu; S G Mills; M MacCoss; L Malkowitz; S Siciliano; S L Gould; J A DeMartino; M S Springer

doi:10.1016/s0960-894x(01)00232-3

1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 1: discovery of the pyrrolidine scaffold and determination of its stereochemical requirements

Bioorg Med Chem Lett. 2001 Jun 4;11(11):1437-40. doi: 10.1016/s0960-894x(01)00232-3.

Authors

J J Hale¹, R J Budhu, S G Mills, M MacCoss, L Malkowitz, S Siciliano, S L Gould, J A DeMartino, M S Springer

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. jeffrey_hale@merck.com

PMID: 11378372
DOI: 10.1016/s0960-894x(01)00232-3

Abstract

A series of 1,3,4-trisubstituted pyrrolidines was discovered to have the ability to displace [(125)I]-MIP-1alpha from the CCR5 receptor expressed on Chinese hamster ovary (CHO) cell membranes. CCR5 activity was found to be dependent on the regiochemistry and the absolute stereochemistry of the pyrrolidine.

MeSH terms

Animals
Binding, Competitive
CCR5 Receptor Antagonists*
CHO Cells
Chemokine CCL4
Cricetinae
Iodine Radioisotopes
Macrophage Inflammatory Proteins / chemistry
Macrophage Inflammatory Proteins / pharmacology
Molecular Conformation
Pyrrolidines / chemistry
Pyrrolidines / pharmacology*
Receptors, CCR5 / genetics
Transfection

Substances

CCR5 Receptor Antagonists
Chemokine CCL4
Iodine Radioisotopes
Macrophage Inflammatory Proteins
Pyrrolidines
Receptors, CCR5