title: Discovery of 3-piperidinyl-1-cyclopentanecarboxamide as a novel scaffold for highly potent CC chemokine receptor 2 antagonists.
abstract: Introduction of ring restrictions to a linear aminobutyramide CC chemokine receptor 2 (CCR2) antagonist lead (2) led to the discovery of a 1,3-disubstituted cyclopentane scaffold with enhanced hCCR2 receptor binding and antagonist activity. (1S,3R)-N-[3,5-Bis(trifluoromethyl)benzyl]-1-methyl-3-[(1R,3'R)-methyl-1'H-spiro[indene-1,4'-piperidin]-1'-yl]cyclopentanecarboxamide (16) had IC50 of 1.3 nM (binding) and 0.45 nM (functional chemotaxis) against hCCR2. It also showed activity against the mouse CCR2 receptor with an IC50 of 130 nM. Compound 16 is selective against other chemokine receptors, including CCR5 ( approximately 500-fold).
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey 07065, USA. lihu_yang@merck.com
authors.forename: Lihu
authors.initials: L
authors.lastname: Yang
authors.forename: Gabor
authors.initials: G
authors.lastname: Butora
authors.forename: Richard X
authors.initials: RX
authors.lastname: Jiao
authors.forename: Alex
authors.initials: A
authors.lastname: Pasternak
authors.forename: Changyou
authors.initials: C
authors.lastname: Zhou
authors.forename: William H
authors.initials: WH
authors.lastname: Parsons
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.forename: Pasquale P
authors.initials: PP
authors.lastname: Vicario
authors.forename: Julia M
authors.initials: JM
authors.lastname: Ayala
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Cascieri
authors.forename: Malcolm
authors.initials: M
authors.lastname: MacCoss
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; D003517:Cyclopentanes; D010880:Piperidines; D054390:Receptors, CCR2; D019707:Receptors, Chemokine