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 t rans-isomer J113863 published by Banyu Pharmaceutical Co., patent WO98/0455 4), which is a potent, selective inhibitor of CCR1 and CCR3. Nanomolar conc entrations of UCB35625 were sufficient to inhibit eosinophil shape change r esponses to MIP-1 alpha; MCP-4, and eotaxin, while greater concentrations c ould inhibit the chemokine induced internalization of both CCR1 and CCR3. U CB35625 also inhibited the CCR3-mediated entry of the human immunodeficienc y virus-1 primary isolate 89.6 into the glial cell line, NP-2 (IC50 = 57 nM ). Chemotaxis of transfected cells expressing either CCR1 or CCR3 was inhib ited by nanomolar concentrations of the compound (IC50 values of CCR1-MIP-1 alpha = 9.6 nM, CCR3-eotaxin = 93.7 nM). However, competitive ligand bindi ng assays on the same transfectants revealed that considerably larger conce ntrations of UCB35625 were needed for effective ligand displacement than we re needed far the inhibition of receptor function. Thus, it appears that th e compound may interact with a region present in both receptors that inhibi ts 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 i nflammatory disorders, such as asthma and as an inhibitor of CCR3-mediated human immunodeficiency virus-1 entry.