1nc6
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(New page: 200px<br /><applet load="1nc6" size="450" color="white" frame="true" align="right" spinBox="true" caption="1nc6, resolution 1.90Å" /> '''Potent, small molecu...)
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Revision as of 20:00, 20 November 2007
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Potent, small molecule inhibitors of human mast cell tryptase. Anti-asthmatic action of a dipeptide-based transition state analogue containing benzothiazole ketone
Overview
Inhibitors 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.
About this Structure
1NC6 is a Single protein structure of sequence from Bos taurus with CA, SO4 and ABB as ligands. Active as Trypsin, with EC number 3.4.21.4 Full crystallographic information is available from OCA.
Reference
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
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