From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part II: Acyclic replacements for the (3S)-3-benzylpiperidine in a series of potent CCR3 antagonists.
Conformational analysis of the 3-benzylpiperidine in CCR3 antagonist clinical candidate 1 (BMS-639623) predicts that the benzylpiperidine may be replaced by acyclic, conformationally stabilized, anti-1,2-disubstituted phenethyl- and phenpropylamines. Ab initio calculations, enantioselective syntheses, and evaluation in CCR3 binding and chemotaxis assays of anti-1-methyl-2-hydroxyphenethyl- and phenpropylamine-containing CCR3 antagonists support this conformational correlation.
Gardner
Daniel S
DS
Bristol-Myers Squibb Company, R & D, PO Box 4000, Princeton, NJ 08543-4000, USA.
Santella
Joseph B
JB
Tebben
Andrew J
AJ
Batt
Douglas G
DG
Ko
Soo S
SS
Traeger
Sarah C
SC
Welch
Patricia K
PK
Wadman
Eric A
EA
Davies
Paul
P
Carter
Percy H
PH
Duncia
John V
JV
D003500:Cyclization; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D054397:Receptors, CCR3 / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
C528978:BMS-639623; C515350:CCR3 protein, human; D010880:Piperidines; D054397:Receptors, CCR3; D014508:Urea