Ch3o

Compounds 4 and 5 have been evaluated in animal models of respiratory disease (39). In ovalbumin-sensitized mice, compound 4 (30-300mg/kg, q.d., p.o.) produced a dose-dependent reduction in bronchial aveolar lavage (BAL) eosinophils and IL-13 collected 24-72 hr after challenge. When compound 4 was administered orally (300 mg/kg) to allergen-challenged mice, there was a reduction in bronchial hyperresponsiveness to inhaled methacholine and an approximate 50% reduction in BAL eosinophils. When Cynomolgus monkeys naturally sensitive to inhaled Ascaris were treated with compound 5 (40 mg/kg, s.c.), they produced a 50% reduction in BAL eosinophils compared to vehicle-treated animals. This report demonstrated that CCR3 blockade partially inhibits eosinophil accumulation in the lung after allergen challenge.

An evaluation of the conformational constraints of the urea-containing tether of compounds 4 and 5 led to a family of compounds exemplified by 6 (IC50 = 1 nM) (4045) . It exhibits functional antagonist activity in blocking eotaxin-induced eosinophil chemotaxis (IC50 = 1.4 nM) and is selective for CCR3 vs. a panel of chemokine receptors. The SAR studies demonstrated that the benzyl group spacing is important for CCR3 specificity vs. CCR1. Optimal conformational/tether-spacing requires ortho phenyl substitution, followed in order of potency by meta and para spacing. The 4-fluoro substituent provides a 3 to 10-fold increase in potency. Interestingly, when some of these compounds are converted to quaternary piperidinium salts, they are transformed from functional antagonists to functional agonists, thus inducing mobilization of Ca2+ and Chemotaxis.

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