From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part I: the discovery of CCR3 antagonist development candidate BMS-639623 with picomolar inhibition potency against eosinophil chemotaxis.
Conformational analysis of trans-1,2-disubstituted cyclohexane CCR3 antagonist 2 revealed that the cyclohexane linker could be replaced by an acyclic syn-alpha-methyl-beta-hydroxypropyl linker. Synthesis and biological evaluation of mono- and disubstituted propyl linkers support this conformational correlation. It was also found that the alpha-methyl group to the urea lowered protein binding and that the beta-hydroxyl group lowered affinity for CYP2D6. Ab initio calculations show that the alpha-methyl group governs the spatial orientation of three key functionalities within the molecule. alpha-Methyl-beta-hydroxypropyl urea 31 with a chemotaxis IC(50)=38 pM for eosinophils was chosen to enter clinical development for the treatment of asthma.
Santella
Joseph B
JB
Bristol-Myers Squibb Company, R&D, PO Box 4000, Princeton, NJ 08543-4000, USA.
Gardner
Daniel S
DS
Yao
Wenqing
W
Shi
Chongsheng
C
Reddy
Prabhakar
P
Tebben
Andrew J
AJ
DeLucca
George V
GV
Wacker
Dean A
DA
Watson
Paul S
PS
Welch
Patricia K
PK
Wadman
Eric A
EA
Davies
Paul
P
Solomon
Kimberly A
KA
Graden
Dani M
DM
Yeleswaram
Swamy
S
Mandlekar
Sandhya
S
Kariv
Ilona
I
Decicco
Carl P
CP
Ko
Soo S
SS
Carter
Percy H
PH
Duncia
John V
JV
D000284:Administration, Oral; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects*; D006860:Hydrogen Bonding; D051379:Mice; D008968:Molecular Conformation; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D054397:Receptors, CCR3 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
C528978:BMS-639623; C515351:Ccr3 protein, mouse; C515352:Ccr3 protein, rat; D065607:Cytochrome P-450 Enzyme Inhibitors; D010880:Piperidines; D054397:Receptors, CCR3; D014508:Urea