Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1.
The CC chemokine receptor-1 (CCR1) is a prime therapeutic target for treating autoimmune diseases. Through high capacity screening followed by chemical optimization, we identified a novel non-peptide CCR1 antagonist, R-N-[5-chloro-2-[2-[4-[(4-fluorophenyl)methyl]-2-methyl-1-piperazinyl ]-2-oxoethoxy]phenyl]urea hydrochloric acid salt (BX 471). Competition binding studies revealed that BX 471 was able to displace the CCR1 ligands macrophage inflammatory protein-1alpha (MIP-1alpha), RANTES, and monocyte chemotactic protein-3 (MCP-3) with high affinity (K(i) ranged from 1 nm to 5.5 nm). BX 471 was a potent functional antagonist based on its ability to inhibit a number of CCR1-mediated effects including Ca(2+) mobilization, increase in extracellular acidification rate, CD11b expression, and leukocyte migration. BX 471 demonstrated a greater than 10,000-fold selectivity for CCR1 compared with 28 G-protein-coupled receptors. Pharmacokinetic studies demonstrated that BX 471 was orally active with a bioavailability of 60% in dogs. Furthermore, BX 471 effectively reduces disease in a rat experimental allergic encephalomyelitis model of multiple sclerosis. This study is the first to demonstrate that a non-peptide chemokine receptor antagonist is efficacious in an animal model of an autoimmune disease. In summary, we have identified a potent, selective, and orally available CCR1 antagonist that may be useful in the treatment of chronic inflammatory diseases.
Liang
M
M
Departments of Discovery Research, Biological Research, Pharmacology, and Immunology, Berlex Biosciences, Richmond, Calfornia 94804, USA. meina_lang@berlex.com
Mallari
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C
Rosser
M
M
Ng
H P
HP
May
K
K
Monahan
S
S
Bauman
J G
JG
Islam
I
I
Ghannam
A
A
Buckman
B
B
Shaw
K
K
Wei
G P
GP
Xu
W
W
Zhao
Z
Z
Ho
E
E
Shen
J
J
Oanh
H
H
Subramanyam
B
B
Vergona
R
R
Taub
D
D
Dunning
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L
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HD
D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D018076:DNA, Complementary; D004285:Dogs; D006801:Humans; D008297:Male; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
C515300:CCR1 protein, human; C515302:Ccr1 protein, rat; D018076:DNA, Complementary; D010671:Phenylurea Compounds; D010880:Piperidines; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; C411885:BX 471