| Abstract
| - Inhibitors of human mast cell tryptase (EC 3.4.21.59) have therapeutic potential for treatingallergic or inflammatory disorders. We have investigated transition-state mimetics possessinga heterocycle-activated ketone group and identified in particular benzothiazole ketone (2S)-6(RWJ-56423) as a potent, reversible, low-molecular-weight tryptase inhibitor with a Ki valueof 10 nM. A single-crystal X-ray analysis of the sulfate salt of (2S)-6 confirmed thestereochemistry. Analogues 12 and 15−17 are also potent tryptase inhibitors. Although RWJ-56423 potently inhibits trypsin (Ki = 8.1 nM), it is selective vs other serine proteases, such askallikrein, plasmin, and thrombin. We obtained an X-ray structure of (2S)-6 complexed withbovine trypsin (1.9-Å resolution), which depicts inter alia a hemiketal involving Ser-189, andhydrogen bonds with His-57 and Gln-192. Aerosol administration of 6 (2R,2S; RWJ-58643) toallergic sheep effectively antagonized antigen-induced asthmatic responses, with 70−75%blockade of the early response and complete ablation of the late response and airwayhyperresponsiveness.
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