title: Identification of dipeptidyl nitriles as potent and selective inhibitors of cathepsin B through structure-based drug design.
abstract: Cathepsin B is a member of the papain superfamily of cysteine proteases and has been implicated in the pathology of numerous diseases, including arthritis and cancer. As part of an effort to identify potent, reversible inhibitors of this protease, we examined a series of dipeptidyl nitriles, starting with the previously reported Cbz-Phe-NH-CH(2)CN (19, IC(50) = 62 microM). High-resolution X-ray crystallographic data and molecular modeling were used to optimize the P(1), P(2), and P(3) substituents of this template. Cathepsin B is unique in its class in that it contains a carboxylate recognition site in the S(2)' pocket of the active site. Inhibitor potency and selectivity were enhanced by tethering a carboxylate functionality from the carbon alpha to the nitrile to interact with this region of the enzyme. This resulted in the identification of compound 10, a 7 nM inhibitor of cathepsin B, with excellent selectivity over other cysteine cathepsins.
authors.affiliation: Arthritis and Bone Metabolism Research, Novartis Pharmaceuticals Corporation, 556 Morris Avenue, Summit, New Jersey 07901, USA. paul.greenspan@pharma.novartis.com
authors.forename: P D
authors.initials: PD
authors.lastname: Greenspan
authors.forename: K L
authors.initials: KL
authors.lastname: Clark
authors.forename: R A
authors.initials: RA
authors.lastname: Tommasi
authors.forename: S D
authors.initials: SD
authors.lastname: Cowen
authors.forename: L W
authors.initials: LW
authors.lastname: McQuire
authors.forename: D L
authors.initials: DL
authors.lastname: Farley
authors.forename: J H
authors.initials: JH
authors.lastname: van Duzer
authors.forename: R L
authors.initials: RL
authors.lastname: Goldberg
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.forename: Z
authors.initials: Z
authors.lastname: Du
authors.forename: J J
authors.initials: JJ
authors.lastname: Fitt
authors.forename: D E
authors.initials: DE
authors.lastname: Coppa
authors.forename: Z
authors.initials: Z
authors.lastname: Fang
authors.forename: W
authors.initials: W
authors.lastname: Macchia
authors.forename: L
authors.initials: L
authors.lastname: Zhu
authors.forename: M P
authors.initials: MP
authors.lastname: Capparelli
authors.forename: R
authors.initials: R
authors.lastname: Goldstein
authors.forename: A M
authors.initials: AM
authors.lastname: Wigg
authors.forename: J R
authors.initials: JR
authors.lastname: Doughty
authors.forename: R S
authors.initials: RS
authors.lastname: Bohacek
authors.forename: A K
authors.initials: AK
authors.lastname: Knap
mesh_terms: D000818:Animals; D001665:Binding Sites; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004151:Dipeptides; D004791:Enzyme Inhibitors; C443681:N-(2-((3-carboxyphenyl)methoxy)-1-cyanoethyl)-3-methyl-Nalpha-(2,4-difluorobenzoyl)phenylalaninamide; D009570:Nitriles; D002401:Cathepsin B