title: Design, synthesis, and evaluation of in vivo potency and selectivity of epoxysuccinyl-based inhibitors of papain-family cysteine proteases.
abstract: The papain-family cathepsins are cysteine proteases that are emerging as promising therapeutic targets for a number of human disease conditions ranging from osteoporosis to cancer. Relatively few selective inhibitors for this family exist, and the in vivo selectivity of most existing compounds is unclear. We present here the synthesis of focused libraries of epoxysuccinyl-based inhibitors and their screening in crude tissue extracts. We identified a number of potent inhibitors that display selectivity for endogenous cathepsin targets both in vitro and in vivo. Importantly, the selectivity patterns observed in crude extracts were generally retained in vivo, as assessed by active-site labeling of tissues from treated animals. Overall, this study identifies several important compound classes and highlights the use of activity-based probes to assess pharmacodynamic properties of small-molecule inhibitors in vivo.
authors.affiliation: Department of Pathology, Stanford School of Medicine, Stanford, CA 94305, USA.
authors.forename: Amir Masoud
authors.initials: AM
authors.lastname: Sadaghiani
authors.forename: Steven H L
authors.initials: SH
authors.lastname: Verhelst
authors.forename: Vasilena
authors.initials: V
authors.lastname: Gocheva
authors.forename: Kimberly
authors.initials: K
authors.lastname: Hill
authors.forename: Eva
authors.initials: E
authors.lastname: Majerova
authors.forename: Sherman
authors.initials: S
authors.lastname: Stinson
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Joyce
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007202:Indicators and Reagents; D007274:Injections, Intraperitoneal; D007441:Intubation, Gastrointestinal; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D010206:Papain / Q000037:antagonists & inhibitors*; D019151:Peptide Library; D040901:Proteomics; D051381:Rats
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004852:Epoxy Compounds; D007202:Indicators and Reagents; D019151:Peptide Library; D010206:Papain