title: Dipeptidyl aspartyl fluoromethylketones as potent caspase inhibitors: peptidomimetic replacement of the P2 alpha-amino acid by a alpha-hydroxy acid.
abstract: As a continuation of our SAR studies of dipeptidyl aspartyl-fmk as caspase inhibitors, we explored the replacement of the P2 alpha-amino acid by a peptidomimetic alpha-hydroxy acid. These alpha-carbamoyl-alkylcarbonyl-aspartyl fluoromethylketones were found to be potent caspase inhibitors, and the SAR of these compounds is similar to the corresponding dipeptidyl aspartyl-fmk. MX1153, (S)-3-methyl-2-(phenylcarbamoyl)butanoyl-Asp-fmk, is identified as a potent broad-spectrum caspase inhibitor, and is selective for caspases versus other proteases. MX1153 also has good activity in the cell apoptosis protection assays and is active in the mouse liver apoptosis model.
authors.affiliation: Maxim Pharmaceuticals, 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Lufeng
authors.initials: L
authors.lastname: Guan
authors.forename: Shaojuan
authors.initials: S
authors.lastname: Jia
authors.forename: Ben
authors.initials: B
authors.lastname: Tseng
authors.forename: John
authors.initials: J
authors.lastname: Drewe
authors.forename: Sui Xiong
authors.initials: SX
authors.lastname: Cai
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001224:Aspartic Acid / Q000737:chemistry; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004151:Dipeptides / Q000737:chemistry; D006801:Humans; D006880:Hydroxy Acids / Q000737:chemistry*; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D006880:Hydroxy Acids; D007659:Ketones; D001224:Aspartic Acid