Bicyclic carbamates as inhibitors of papain-like cathepsin proteases.
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.
Epple
Robert
R
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
Urbina
Hugo D
HD
Russo
Ross
R
Liu
Hong
H
Mason
Daniel
D
Bursulaya
Badry
B
Tumanut
Christine
C
Li
Jun
J
Harris
Jennifer L
JL
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
D019086:Bridged Bicyclo Compounds, Heterocyclic; D002219:Carbamates; D002403:Cathepsins; D010206:Papain