Discovery of novel non-peptide CCR1 receptor antagonists.
Ligands for the CCR1 receptor (MIP-1alpha and RANTES) have been implicated in a number of chronic inflammatory diseases, most notably multiple sclerosis and rheumatoid arthritis. Because these ligands share a common receptor, CCR1, we sought to discover antagonists for this receptor as an approach to treating these disorders. A novel series of 4-hydroxypiperidines has been discovered by high throughput screening (HTS) which potently inhibits the binding of MIP-1alpha and RANTES to the recombinant human CCR1 chemokine receptor. The structure-activity relationships of various segments of this template are described as the initial HTS lead 1 was optimized synthetically to the highly potent receptor antagonist 6s. This compound has been shown to have at least 200-fold selectivity for inhibition of CCR1 over other human 7-TM receptors, including other chemokine receptors. In addition, data obtained from in vitro functional assays demonstrate the functional antagonism of compound 6s and structurally related analogues against the CCR1 receptor in a concentration dependent manner. The discovery and optimization of potent and selective CCR1 receptor antagonists represented by compound 6s potentially represent a novel approach to the treatment of chronic inflammatory diseases.
Ng
H P
HP
Department of Discovery Research, Berlex Biosciences, 15049 San Pablo Avenue, Richmond, California 94804-0099, USA.
May
K
K
Bauman
J G
JG
Ghannam
A
A
Islam
I
I
Liang
M
M
Horuk
R
R
Hesselgesser
J
J
Snider
R M
RM
Perez
H D
HD
Morrissey
M M
MM
D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism / Q000494:pharmacology; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
C401389:4-(4-chlorophenyl)-4-hydroxy-alpha,alpha-diphenyl-1-piperidinepentanenitrile; D000893:Anti-Inflammatory Agents; C515300:CCR1 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019402:Macrophage Inflammatory Proteins; D009570:Nitriles; D010880:Piperidines; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D002118:Calcium