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

Yan Wang; Shaojuan Jia; Ben Tseng; John Drewe; Sui Xiong Cai

doi:10.1016/j.bmcl.2007.09.030

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

Bioorg Med Chem Lett. 2007 Nov 15;17(22):6178-82. doi: 10.1016/j.bmcl.2007.09.030. Epub 2007 Sep 8.

Authors

Yan Wang¹, Shaojuan Jia, Ben Tseng, John Drewe, Sui Xiong Cai

Affiliation

¹ EpiCept Corporation, 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.

PMID: 17889532
DOI: 10.1016/j.bmcl.2007.09.030

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.

MeSH terms

Amino Acids / chemistry*
Apoptosis / drug effects
Aspartic Acid / chemistry
Benzamides / chemistry
Benzamides / pharmacology*
Caspase Inhibitors*
Caspases / chemistry
Dipeptides / chemical synthesis
Dipeptides / chemistry
Dipeptides / pharmacology*
Drug Evaluation, Preclinical
Fluorine / chemistry
HeLa Cells
Humans
Inhibitory Concentration 50
Ketones / chemistry
Ketones / pharmacology*
Molecular Mimicry*
Molecular Structure
Structure-Activity Relationship

Substances

Amino Acids
Benzamides
Caspase Inhibitors
Dipeptides
Ketones
Z-Val-(2-aminobenzoyl)-Asp-fluoromethyl ketone
Fluorine
Aspartic Acid
Caspases