title: Conformational studies of 3-amino-1-alkyl-cyclopentane carboxamide CCR2 antagonists leading to new spirocyclic antagonists.
abstract: In an effort to shed light on the active binding conformation of our 3-amino-1-alkyl-cyclopentane carboxamide CCR2 antagonists, we prepared several conformationally constrained analogs resulting from backbone cyclization. Evaluation of CCR2 binding affinities for these analogs gave insight into the optimal relative positions of the piperidine and benzylamide moieties while simultaneously leading to the discovery of a new, potent lead type based upon a spirocyclic acetal scaffold.
authors.affiliation: Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pasternak
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Goble
authors.forename: George A
authors.initials: GA
authors.lastname: Doss
authors.forename: Nancy N
authors.initials: NN
authors.lastname: Tsou
authors.forename: Gabor
authors.initials: G
authors.lastname: Butora
authors.forename: Pasquale P
authors.initials: PP
authors.lastname: Vicario
authors.forename: Julia Marie
authors.initials: JM
authors.lastname: Ayala
authors.forename: Mary
authors.initials: M
authors.lastname: Struthers
authors.forename: Julie A
authors.initials: JA
authors.lastname: Demartino
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.forename: Lihu
authors.initials: L
authors.lastname: Yang
mesh_terms: D000080:Acetals / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003517:Cyclopentanes / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008968:Molecular Conformation; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000080:Acetals; D003517:Cyclopentanes; D054390:Receptors, CCR2; D013141:Spiro Compounds