Medicinal Chemistry

Through screening of compound collections, selective CCR3 antagonist designs containing arylpiperidine motifs linked by a tether of three to six atoms to a second aromatic group have been identified. Xanthenecarboxamide UCB35625 1 , potently inhibits binding of 125l-eotaxin to human CCR3 (IC50 = 0.58 nM) and "^l-MIP-la binding to human CCR1 (IC50 = 0.9 nM) (31). In functional studies, compound 1 inhibits eotaxin-induced chemotaxis of murine pre-B 4DEA4 cells transfected with CCR3 (IC50 = 93 nM) and MIP-1a-induced chemotaxis with 4DEA4 cells transfected with CCR1 (32). To improve selectivity for CCR3 and to eliminate the quaternary ammonium group of 1, a library designed using clustering techniques to optimize diversity identified benzothiazolethioactamides 2_and_3 (33).

Compound 2 is 800-fold selective for CCR3 (IC50 = 2.3 nM) vs. CCR1 (IC50 = 1900 nM). In functional studies with human peripheral blood eosinophils, compound 2 inhibits eotaxin-induced (10 nM) increases in intracellular Ca2+ (IC50 = 27 nM) and eotaxin-induced chemotaxis of human eosinophils (IC50 = 21 nM) (34). The acetamide 3 is more selective for CCR3 (IC50 = 1 -5 nM) vs. CCR1 (IC50 = 5400 nM) (35).

In a second variation of the arylpiperidine design, a urea group comprises a portion of the tether. R01164875/608 4 and R03202947/001 5 inhibit 125l-eotaxin binding (IC50 = 59 nM and 1.4 nM, respectively), and eotaxin-induced eosinophil chemotaxis IC50 = 4.9 nM and 1.8 nM, respectively) (36-38).

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