Nicotinyl aspartyl ketones as inhibitors of caspase-3

  • Bioorg Med Chem Lett. 2003 Jul 7;13(13):2137-40. doi: 10.1016/s0960-894x(03)00390-1.
Elise Isabel  1 ,  W Cameron Black ,  Christopher I Bayly ,  Erich L Grimm ,  Marc K Janes ,  Daniel J McKay ,  Donald W Nicholson ,  Dita M Rasper ,  Johanne Renaud ,  Sophie Roy ,  John Tam ,  Nancy A Thornberry ,  John P Vaillancourt ,  Steven Xanthoudakis ,  Robert Zamboni
Affiliations
  • 1. Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada & Co., Pointe-Claire-Dorval, H9R 4P8, Quebec, Canada. [email protected]
PMID: 12798321 DOI: 10.1016/s0960-894x(03)00390-1
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.