1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 1: discovery of the pyrrolidine scaffold and determination of its stereochemical requirements.
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.
Hale
J J
JJ
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. jeffrey_hale@merck.com
Budhu
R J
RJ
Mills
S G
SG
MacCoss
M
M
Malkowitz
L
L
Siciliano
S
S
Gould
S L
SL
DeMartino
J A
JA
Springer
M S
MS
D000818:Animals; D001667:Binding, Competitive; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D054407:Chemokine CCL4; D006224:Cricetinae; D007457:Iodine Radioisotopes; D019402:Macrophage Inflammatory Proteins / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000235:genetics; D014162:Transfection
D065100:CCR5 Receptor Antagonists; D054407:Chemokine CCL4; D007457:Iodine Radioisotopes; D019402:Macrophage Inflammatory Proteins; D011759:Pyrrolidines; D019713:Receptors, CCR5