title: 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.
abstract: 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.
authors: Bristol-Myers Squibb Company, R&D, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors: Joseph B
authors: JB
authors: Santella
authors: Daniel S
authors: DS
authors: Gardner
authors: Wenqing
authors: W
authors: Yao
authors: Chongsheng
authors: C
authors: Shi
authors: Prabhakar
authors: P
authors: Reddy
authors: Andrew J
authors: AJ
authors: Tebben
authors: George V
authors: GV
authors: DeLucca
authors: Dean A
authors: DA
authors: Wacker
authors: Paul S
authors: PS
authors: Watson
authors: Patricia K
authors: PK
authors: Welch
authors: Eric A
authors: EA
authors: Wadman
authors: Paul
authors: P
authors: Davies
authors: Kimberly A
authors: KA
authors: Solomon
authors: Dani M
authors: DM
authors: Graden
authors: Swamy
authors: S
authors: Yeleswaram
authors: Sandhya
authors: S
authors: Mandlekar
authors: Ilona
authors: I
authors: Kariv
authors: Carl P
authors: CP
authors: Decicco
authors: Soo S
authors: SS
authors: Ko
authors: Percy H
authors: PH
authors: Carter
authors: John V
authors: JV
authors: Duncia
mesh_terms: 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
chemical_list: C528978:BMS-639623; C515351:Ccr3 protein, mouse; C515352:Ccr3 protein, rat; D065607:Cytochrome P-450 Enzyme Inhibitors; D010880:Piperidines; D054397:Receptors, CCR3; D014508:Urea