Conformational studies of 3-amino-1-alkyl-cyclopentane carboxamide CCR2 antagonists leading to new spirocyclic antagonists.
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.
Pasternak
Alexander
A
Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA.
Goble
Stephen D
SD
Doss
George A
GA
Tsou
Nancy N
NN
Butora
Gabor
G
Vicario
Pasquale P
PP
Ayala
Julia Marie
JM
Struthers
Mary
M
Demartino
Julie A
JA
Mills
Sander G
SG
Yang
Lihu
L
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
D000080:Acetals; D003517:Cyclopentanes; D054390:Receptors, CCR2; D013141:Spiro Compounds