General solid-phase method to prepare novel cyclic ketone inhibitors of the cysteine protease cruzain.
A series of constrained ketone-based inhibitors has been developed that show low nanomolar Ki values. These ketone inhibitors showed promising activity towards cruzain, the cysteine protease implicated in Chagas' disease. This series of constrained inhibitors, which can be accessed quickly and efficiently using a solid-phase combinatorial strategy, should be applicable to other members of the cysteine protease class.
Huang
Lily
L
Center for New Directions in Organic Synthesis, Department of Chemistry, University of California, Berkeley, CA 94720, USA.
Ellman
Jonathan A
JA
D002401:Cathepsin B / Q000037:antagonists & inhibitors; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000494:pharmacology; D007700:Kinetics; D008968:Molecular Conformation; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D015853:Cysteine Proteinase Inhibitors; D007659:Ketones; D015800:Protozoan Proteins; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L