CCR3 antagonists where the piperidine ring is replaced by a morpholine are exemplified by compounds 17 and 18 (63-64). Compound 17 Is a potent inhibitor in the CCR3 binding assay (IC50 = 4.1 nM). In ovalbumin-sensitized guinea pigs, compound 18 (CCR3 binding IC50 = 660 nM; 0.2-20 mg/kg, p.o.) produced inhibition of lung eoslnophilia and bronchial hyperreactivitiy (64).
A novel structural class comprising a pyrrolo-[3,4-c]pyrrolidine tether/linker is illustrated by compounds 19 and 20 (65). The selectivity of this series was evaluated for Inhibition of eotaxin-induced chemotaxis in murine pre-B cells transfected with CCR3 and in MCP 1-induced chemotaxis in THP-1 monocytes. In general, compounds where R = CH3 were selective for the CCR2 receptor and compounds where R = CI were selective for the CCR3 receptor. Analogs of 20 completely blocked the binding of eotaxin to the CCR3 receptor in murine pre-B cells transfected with CCR3 at 1 uM.
Urea analogs 21 and 22 that completely block eotaxin-induced chemotaxis at 10 uM concentrations, suppress type II collagen-induced arthritis in mice at 50 mg/kg s.c. and 20 mg/kg s.c., respectively (66). In ovalbumin-sensitized mice, compound 21 (50 mg/kg, i.p.) produced a reduction in bronchial hyperresponsiveness to injected acetyl choline and an approximate 50% reduction in BAL eosinophils.
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