title: Nicotinyl aspartyl ketones as inhibitors of caspase-3.
abstract: Caspase-3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact in the treatment of several degenerative diseases. Since P(1) aspartic acid is a required element of recognition for this enzyme, a library of capped aspartyl aldehydes was synthesized using solid-phase chemistry. The 5-bromonicotinamide derivative of the aspartic acid aldehyde was identified to be an inhibitor of caspase-3. Substitution at the 5-position of the pyridine ring and conversion of the aldehyde to ketones led to a series of potent inhibitors of caspase-3.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada & Co., Pointe-Claire-Dorval, H9R 4P8, Quebec, Canada. elise_isabel@merck.com
authors.forename: Elise
authors.initials: E
authors.lastname: Isabel
authors.forename: W Cameron
authors.initials: WC
authors.lastname: Black
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Bayly
authors.forename: Erich L
authors.initials: EL
authors.lastname: Grimm
authors.forename: Marc K
authors.initials: MK
authors.lastname: Janes
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: McKay
authors.forename: Donald W
authors.initials: DW
authors.lastname: Nicholson
authors.forename: Dita M
authors.initials: DM
authors.lastname: Rasper
authors.forename: Johanne
authors.initials: J
authors.lastname: Renaud
authors.forename: Sophie
authors.initials: S
authors.lastname: Roy
authors.forename: John
authors.initials: J
authors.lastname: Tam
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Thornberry
authors.forename: John P
authors.initials: JP
authors.lastname: Vaillancourt
authors.forename: Steven
authors.initials: S
authors.lastname: Xanthoudakis
authors.forename: Robert
authors.initials: R
authors.lastname: Zamboni
mesh_terms: D000447:Aldehydes / Q000138:chemical synthesis / Q000494:pharmacology; D001224:Aspartic Acid / Q000737:chemistry; D053148:Caspase 3; D061945:Caspase Inhibitors; D002460:Cell Line; D053938:DNA Fragmentation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007202:Indicators and Reagents; D007659:Ketones / Q000138:chemical synthesis* / Q000494:pharmacology*; D019151:Peptide Library; D011725:Pyridines / Q000737:chemistry
chemical_list: D000447:Aldehydes; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D007659:Ketones; D019151:Peptide Library; D011725:Pyridines; D001224:Aspartic Acid; C505407:CASP3 protein, human; D053148:Caspase 3