A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry.
We describe a small molecule chemokine receptor antagonist, UCB35625 (the trans-isomer J113863 published by Banyu Pharmaceutical Co., patent WO98/04554), which is a potent, selective inhibitor of CCR1 and CCR3. Nanomolar concentrations of UCB35625 were sufficient to inhibit eosinophil shape change responses to MIP-1alpha, MCP-4, and eotaxin, while greater concentrations could inhibit the chemokine-induced internalization of both CCR1 and CCR3. UCB35625 also inhibited the CCR3-mediated entry of the human immunodeficiency virus-1 primary isolate 89.6 into the glial cell line, NP-2 (IC(50) = 57 nm). Chemotaxis of transfected cells expressing either CCR1 or CCR3 was inhibited by nanomolar concentrations of the compound (IC(50) values of CCR1-MIP-1alpha = 9.6 nm, CCR3-eotaxin = 93.7 nm). However, competitive ligand binding assays on the same transfectants revealed that considerably larger concentrations of UCB35625 were needed for effective ligand displacement than were needed for the inhibition of receptor function. Thus, it appears that the compound may interact with a region present in both receptors that inhibits the conformational change necessary to initiate intracellular signaling. By virtue of its potency at the two major eosinophil chemokine receptors, UCB35625 is a prototypic therapy for the treatment of eosinophil-mediated inflammatory disorders, such as asthma and as an inhibitor of CCR3-mediated human immunodeficiency virus-1 entry.
Sabroe
I
I
Leukocyte Biology Section, Biomedical Sciences Division, Sir Alexander Fleming Building, Imperial College School of Medicine, South Kensington, London SW7 2AZ, United Kingdom.
Peck
M J
MJ
Van Keulen
B J
BJ
Jorritsma
A
A
Simmons
G
G
Clapham
P R
PR
Williams
T J
TJ
Pease
J E
JE
D000818:Animals; D054413:Chemokine CCL11; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D016207:Cytokines / Q000494:pharmacology; D004347:Drug Interactions; D004804:Eosinophils / Q000187:drug effects / Q000502:physiology*; D005434:Flow Cytometry; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D051379:Mice; D008956:Models, Chemical; D018945:Monocyte Chemoattractant Proteins / Q000494:pharmacology; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism*; D014162:Transfection; D014966:Xanthenes / Q000494:pharmacology*
C515456:CCL11 protein, human; C099677:CCL13 protein, human; C515300:CCR1 protein, human; C515350:CCR3 protein, human; C515457:Ccl11 protein, mouse; C515301:Ccr1 protein, mouse; C515351:Ccr3 protein, mouse; D054413:Chemokine CCL11; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D018945:Monocyte Chemoattractant Proteins; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D014966:Xanthenes; C413447:UCB 35625