2,4-Disubstituted piperidines as selective CC chemokine receptor 3 (CCR3) antagonists: synthesis and selectivity.
Linear unselective CCR3 antagonist leads with IC(50) values in the 200 nM range were converted into low nM binding compounds selective at CCR3 by moving the piperidine nitrogen substituent to the carbon at the 2-position of the ring. Substitution of the piperidine nitrogen with simple alkyl and acyl groups was found to improve the selectivity of this new compound class. In particular, N-{3-[(2S, 4R)-1-(propyl)-4-(4-fluorobenzyl)piperidinyl]propyl}-N'-(3-acetylphenyl)urea exhibited single digit nanomolar IC(50) values for CCR3 with >100-fold selectivity against an extensive counter screen panel.
Watson
Paul S
PS
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08542-5400, USA. pwatson@inspirepharm.com
Jiang
Bin
B
Harrison
Kim
K
Asakawa
Nao
N
Welch
Patricia K
PK
Covington
Maryanne
M
Stowell
Nicole C
NC
Wadman
Eric A
EA
Davies
Paul
P
Solomon
Kimberly A
KA
Newton
Robert C
RC
Trainor
George L
GL
Friedman
Steven M
SM
Decicco
Carl P
CP
Ko
Soo S
SS
D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D010880:Piperidines; D054397:Receptors, CCR3; D019707:Receptors, Chemokine