title: Identification of selective, nonpeptidic nitrile inhibitors of cathepsin s using the substrate activity screening method.
abstract: The substrate activity screening method, a substrate-based fragment identification and optimization method for the development of enzyme inhibitors, was previously applied to cathepsin S to obtain low nanomolar 1,4-disubstituted-1,2,3-triazole-based aldehyde inhibitors (Wood, W. J. L.; Patterson, A. W.; Tsuruoka, H.; Jain, R. K.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 15521-15527). Replacement of the metabolically labile aldehyde pharmacophore with the nitrile pharmacophore provided inhibitors with moderate potency for cathepsin S. The inhibitors showed good selectivity over cathepsins B and L but no selectivity over cathepsin K. X-ray structures of two crystal forms (1.5 and 1.9 A) of a complex between cathepsin S and a triazole inhibitor incorporating a chloromethyl ketone pharmacophore guided the design of triazole substrates with increased cleavage efficiency and selectivity for cathepsin S over cathepsins B, L, and K. Conversion of select substrates to nitrile inhibitors yielded a low molecular weight (414 Da) and potent (15 nM) cathepsin S inhibitor that showed >1000-fold selectivity over cathepsins B, L, and K.
authors.affiliation: Department of Chemistry, University of California, Berkeley, California 94720, USA.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Patterson
authors.forename: Warren J L
authors.initials: WJ
authors.lastname: Wood
authors.forename: Michael
authors.initials: M
authors.lastname: Hornsby
authors.forename: Scott
authors.initials: S
authors.lastname: Lesley
authors.forename: Glen
authors.initials: G
authors.lastname: Spraggon
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Ellman
mesh_terms: D000595:Amino Acid Sequence; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D009570:Nitriles; D011480:Protease Inhibitors; D014230:Triazoles; D002403:Cathepsins; C028217:cathepsin S