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Bicyclic carbamates as inhibitors of papain-like cathepsin proteases.

Epple, Robert, Urbina, Hugo, Russo, Ross, Liu, Hong, Mason, Daniel, Bursulaya, Badry, Tumanut, Christine, Li, Jun and Harris, Jennifer (2007) Bicyclic carbamates as inhibitors of papain-like cathepsin proteases. Bioorganic & Medicinal Chemistry Letters, 17 (5). pp. 1254-1259. ISSN 0960-894X


A 6-oxa-1-aza-bicyclo[3.2.1]octan-7-one system inhibits the proteolytic activity of several cysteine proteases belonging to the papain family. In vitro mechanistic studies and in silico calculations suggest that the minimal pi-overlap between the bridgehead nitrogen and the carbonyl leads to a considerable weakening of the urethane system, making it susceptible to nucleophilic attack from the active site thiol group. The resulting covalent adduct is slowly hydrolyzed, releasing the hydroxypiperidine product of the inhibitor. Synthesis and testing of a set of analogs led to variable protease subtype selectivities ranging from micromolar to nanomolar potencies.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: Cathepsins; Protease inhibitors; Carbamates
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Date Deposited: 14 Dec 2009 14:05
Last Modified: 31 Jan 2013 01:27


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