Identification and characterization of small molecule functional antagonists of the CCR1 chemokine receptor.
The CC chemokines macrophage inflammatory protein-1alpha (MIP-1alpha) and RANTES (regulated on activation normal T cell expressed) have been implicated in rheumatoid arthritis and multiple sclerosis. Since their effects are mediated through the CCR1 chemokine receptor, we set up a small molecule CCR1 antagonist program to search for inhibitors. Through high capacity screening we discovered a number of 4-hydroxypiperidine compounds with CCR1 antagonist activity and report their synthesis and in vitro pharmacology here. Scatchard analysis of the competition binding data revealed that the compounds had Ki values ranging from 40 to 4000 nM. The pharmacological profile of the most potent member of this series, compound 1 (2-2-diphenyl-5-(4-chlorophenyl)piperidin-lyl)valeronitri te), was further evaluated. Compound 1 showed concentration-dependent inhibition of MIP-1alpha-induced extracellular acidification and Ca2+ mobilization demonstrating functional antagonism. When given alone, the compound did not elicit any responses, indicating the absence of intrinsic agonist activity. Compound 1 inhibited MIP-1alpha- and RANTES-induced migration in peripheral blood mononuclear cells in a dose-responsive manner. Selectivity testing against a panel of seven transmembrane domain receptors indicated that compound 1 is inactive on a number of receptors at concentrations up to 10 microM. This is the first description of CCR1 receptor antagonists that may be useful in the treatment of chronic inflammatory diseases involving MIP-1alpha, RANTES, and CCR1.
Hesselgesser
J
J
Department of Immunology, Berlex BioSciences, Richmond, California 94806, USA.
Ng
H P
HP
Liang
M
M
Zheng
W
W
May
K
K
Bauman
J G
JG
Monahan
S
S
Islam
I
I
Wei
G P
GP
Ghannam
A
A
Taub
D D
DD
Rosser
M
M
Snider
R M
RM
Morrissey
M M
MM
Perez
H D
HD
Horuk
R
R
D001172:Arthritis, Rheumatoid / Q000503:physiopathology; D002460:Cell Line; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D008024:Ligands; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D009103:Multiple Sclerosis / Q000503:physiopathology; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*
C515300:CCR1 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D008024:Ligands; D019402:Macrophage Inflammatory Proteins; D010880:Piperidines; D054389:Receptors, CCR1; D019707:Receptors, Chemokine