Discovery of a novel CCR3 selective antagonist

In searching for a novel CCR3 receptor antagonist, we designed a library th at included a variety of carboxamide derivatives based on the structure of our potent antagonists for human CCR1 and CCR3 receptors, and screened the new compounds for inhibitory actitity against I-125-Eotaxin binding to huma n CCR3 receptors expressed in CHO cells. Among them, two 2-(benzothiazoleth io)acetamide derivatives (1a and 2a) showed binding affinities with IC50 va lues of 750 and 1000 nM respectively, for human CCR3 receptors. These compo unds (1a and 2a) also possessed weak binding affinities for human CCR1 rece ptors. We selected la as a lead compound for derivatization to improve in v itro potency and selectivity for CCR3 over CCR1 receptors. Derivatization o f la by incorporating substituents into each benzene ring of the benzothiaz ole and piperidine side chain resulted in the discovery of a compound (1b) exhibiting 820-fold selectivity for CCR3 receptors (IC50 = 2.3 nM) over CCR 1 receptors (IC50-1900nM). This compound (1b) also showed potent functional antagonist activity for inhibiting Eotaxin (IC50 = 27 nM)- or RANTES (IC50 = 13 nM)-induced Ca2+ increases in eosinophils. (C) 2001 Elsevier Science Ltd. All rights reserved.