Discovery and lead optimization of a novel series of CC chemokine receptor 1 (CCR1)-selective piperidine antagonists via parallel synthesis.
A series of novel, potent CCR1 inhibitors was developed from a moderately active hit using an iterative parallel synthesis approach. The initial hit (composed of three subunits: an amine, a central amino acid, and an N-terminal cap) became the basis for a series of parallel chemical libraries designed to generate SAR data. Libraries were synthesized that explored each of the three subunits; the CCR1 binding data obtained revealed the following: (1) changes to the amine are not well tolerated; (2) small alkylamino acids are preferred in the center of the molecule; (3) substitutions at the N-terminus are generally well tolerated. These data were used to drive the optimization of the series, ultimately providing a lead with a CCR1 binding IC(50) of 28 nM (48). This lead demonstrates high selectivity for CCR1 over other CCR-family members, high microsomal stability, and good pharmacokinetics in mice.
Research and Development, Bristol-Myers Squibb Company, Route 206 and Provinceline Road, Princeton, New Jersey 08540, USA. cullen.cavallaro@bms.com
Cullen L
CL
Cavallaro
Stephanie
S
Briceno
Jing
J
Chen
Mary Ellen
ME
Cvijic
Paul
P
Davies
John
J
Hynes
Rui-Qin
RQ
Liu
Sandhya
S
Mandlekar
Anne V
AV
Rose
Andrew J
AJ
Tebben
Katy
K
Van Kirk
Andrew
A
Watson
Hong
H
Wu
Guchen
G
Yang
Percy H
PH
Carter
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D054388:Receptors, CCR / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D010880:Piperidines; D054388:Receptors, CCR; C032727:piperidine; D002118:Calcium