1nc6
From Proteopedia
Potent, small molecule inhibitors of human mast cell tryptase. Anti-asthmatic action of a dipeptide-based transition state analogue containing benzothiazole ketone
Structural highlights
FunctionEvolutionary ConservationCheck, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedInhibitors of human mast cell tryptase (EC 3.4.21.59) have therapeutic potential for treating allergic or inflammatory disorders. We have investigated transition-state mimetics possessing a 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 K(i) value of 10 nM. A single-crystal X-ray analysis of the sulfate salt of (2S)-6 confirmed the stereochemistry. Analogues 12 and 15-17 are also potent tryptase inhibitors. Although RWJ-56423 potently inhibits trypsin (K(i) = 8.1 nM), it is selective vs other serine proteases, such as kallikrein, plasmin, and thrombin. We obtained an X-ray structure of (2S)-6 complexed with bovine trypsin (1.9-A resolution), which depicts inter alia a hemiketal involving Ser-189, and hydrogen bonds with His-57 and Gln-192. Aerosol administration of 6 (2R,2S; RWJ-58643) to allergic sheep effectively antagonized antigen-induced asthmatic responses, with 70-75% blockade of the early response and complete ablation of the late response and airway hyperresponsiveness. Potent, small-molecule inhibitors of human mast cell tryptase. Antiasthmatic action of a dipeptide-based transition-state analogue containing a benzothiazole ketone.,Costanzo MJ, Yabut SC, Almond HR Jr, Andrade-Gordon P, Corcoran TW, De Garavilla L, Kauffman JA, Abraham WM, Recacha R, Chattopadhyay D, Maryanoff BE J Med Chem. 2003 Aug 28;46(18):3865-76. PMID:12930148[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations 8 reviews cite this structure No citations found See AlsoReferences
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