title: 2,4-Disubstituted piperidines as selective CC chemokine receptor 3 (CCR3) antagonists: synthesis and selectivity.
abstract: 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.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08542-5400, USA. pwatson@inspirepharm.com
authors.forename: Paul S
authors.initials: PS
authors.lastname: Watson
authors.forename: Bin
authors.initials: B
authors.lastname: Jiang
authors.forename: Kim
authors.initials: K
authors.lastname: Harrison
authors.forename: Nao
authors.initials: N
authors.lastname: Asakawa
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Welch
authors.forename: Maryanne
authors.initials: M
authors.lastname: Covington
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Stowell
authors.forename: Eric A
authors.initials: EA
authors.lastname: Wadman
authors.forename: Paul
authors.initials: P
authors.lastname: Davies
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Solomon
authors.forename: Robert C
authors.initials: RC
authors.lastname: Newton
authors.forename: George L
authors.initials: GL
authors.lastname: Trainor
authors.forename: Steven M
authors.initials: SM
authors.lastname: Friedman
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
authors.forename: Soo S
authors.initials: SS
authors.lastname: Ko
mesh_terms: D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D010880:Piperidines; D054397:Receptors, CCR3; D019707:Receptors, Chemokine