title: Bicyclic carbamates as inhibitors of papain-like cathepsin proteases.
abstract: 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.
authors.affiliation: Department of Drug Discovery, The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA. repple@gnf.org
authors.forename: Robert
authors.initials: R
authors.lastname: Epple
authors.forename: Hugo D
authors.initials: HD
authors.lastname: Urbina
authors.forename: Ross
authors.initials: R
authors.lastname: Russo
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Daniel
authors.initials: D
authors.lastname: Mason
authors.forename: Badry
authors.initials: B
authors.lastname: Bursulaya
authors.forename: Christine
authors.initials: C
authors.lastname: Tumanut
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Harris
mesh_terms: D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology*; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D019295:Computational Biology; D004583:Electrons; D008958:Models, Molecular; D010206:Papain / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D002219:Carbamates; D002403:Cathepsins; D010206:Papain