Structure-activity relationships of 2-(benzothiazolylthio)acetamide class of CCR3 selective antagonist.

The structure activity relationships of novel selective CCR3 receptor antagonists, 2-(benzothiazolylthio)acetamimde derivatives were described. A lead structure (1a) was discovered from the screening of the focused library that was based on the structure of our dual antagonists for the human CCR1 and CCR3 receptors. Derivatization of 1a including incorporation of substituent(s) into each benzene ring of the benzothiazole and piperidine side chain resulted in the identification of potent and selective compounds (1b, r, s) exhibiting nano-molar binding affinity (IC(50)s: 1.5-3.0 nM) and greater than 800-fold selectivity for the CCR3 receptor over the CCR1 receptor.

CCR1 chemokine receptor antagonist.

The selective accumulation and activation of leukocytes in inflamed tissues contributes to the pathogenesis of inflammatory and autoimmune diseases such as infection, rheumatoid arthritis, allergic asthma, atopic dermatitis, and multiple sclerosis. A substantial body of reports suggests that chemokines and their receptors, which belong to a family of seven transmembrane G-protein coupled receptors (GPCR), may be involved in the selective accumulation and activation of leukocytes in inflamed tissues, and in the pathogenesis of inflammatory and autoimmune diseases. One such receptor is CCR1 which is a receptor for CC chemokines, such as CCL5 (RANTES) and CCL3 (MIP-1alpha). The involvement of CCR1 in immunological diseases now is documented in several preclinical studies with CCR1 deficient mice, anti-CCR1 antibodies and CCR1 antagonists, suggesting that CCR1 may be an attractive therapeutic target for a variety of diseases. Publications and patents describing CCR1 antagonists and their pharmacological effects have recently been disclosed. This review highlights the biology and pathophysiology of CCR1, and some of its currently reported antagonists. Additionally, our approach to CCR1 drug discovery is summarized.

Structure-activity relationships of xanthene carboxamides, novel CCR1 receptor antagonists.

The structure-activity relationships of xanthene carboxamide derivatives on the CCR1 receptor binding affinity and the functional antagonist activity were described. Previously, we reported a quaternarized xanthen-9-carboxamide 1 as a potent human CCR1 receptor antagonist that was derived from a xanthen-9-carboxamide lead 2a. Further derivatization of 2a focusing on installing an additional substituent into the xanthene ring resulted in the identification of 2b-1 with IC(50) values of 1.8nM and 13nM in the binding assay using human CCR1 receptors transfected CHO cells and in the functional assay using U937 cells expressing human CCR1 receptors, respectively.

Eotaxin induces migration of RBL-2H3 mast cells via a Rac-ERK-dependent pathway.

Eotaxin is a potent chemokine that acts via CC chemokine receptor 3 (CCR3) to induce chemotaxis, mainly on eosinophils. Here we show that eotaxin also induces chemotactic migration in rat basophilic leukemia (RBL-2H3) mast cells. This effect was dose-dependently inhibited by compound X, a selective CCR3 antagonist, indicating that, as in eosinophils, the effect was mediated by CCR3. Eotaxin-induced cell migration was completely blocked in RBL-RacN17 cells expressing a dominant negative Rac1 mutant, suggesting a crucial role for Rac1 in eotaxin signaling to chemotactic migration. ERK activation also proved essential for eotaxin signaling and it too was absent in RBL-RacN17 cells. Finally, we found that activation of Rac and ERK was correlated with eotaxin-induced actin reorganization known to be necessary for cell motility. It thus appears that Rac1 acts upstream of ERK to signal chemotaxis in these cells, and that a Rac-ERK-dependent cascade mediates the eotaxin-induced chemotactic motility of RBL-2H3 mast cells.