title: Dipeptidyl aspartyl fluoromethylketones as potent caspase inhibitors: peptidomimetic replacement of the P(2) amino acid by 2-aminoaryl acids and other non-natural amino acids.
abstract: As a continuation of our SAR studies of dipeptidyl aspartyl-fmk as caspase inhibitors, we explored the replacement of the P(2) amino acid by a 2-aminoaryl acid or other non-natural amino acids. Several of these compounds, such as 6l and 6p, were found to have good activities with inhibition potencies of around 100 nM in a caspase-3 enzyme assay. EP1113, Z-Val-(2-aminobenzoyl)-Asp-fmk (9b), is identified as a potent broad-spectrum caspase inhibitor with IC(50) values of 6-60 nM in different caspases. EP1113 also has good activity in a cell apoptosis protection assay.
authors: EpiCept Corporation, 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors: Yan
authors: Y
authors: Wang
authors: Shaojuan
authors: S
authors: Jia
authors: Ben
authors: B
authors: Tseng
authors: John
authors: J
authors: Drewe
authors: Sui Xiong
authors: SX
authors: Cai
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D017209:Apoptosis / Q000187:drug effects; D001224:Aspartic Acid / Q000737:chemistry; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D005461:Fluorine / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology*; D018716:Molecular Mimicry; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D001549:Benzamides; D061945:Caspase Inhibitors; D004151:Dipeptides; D007659:Ketones; C527750:Z-Val-(2-aminobenzoyl)-Asp-fluoromethyl ketone; D005461:Fluorine; D001224:Aspartic Acid; D020169:Caspases