N-Acyl aspartic acid ketones (3a-3n) were prepared from the corresponding bromomethyl ketone. The inhibition of interleukin-lJ3 converting enzyme (ICE) by these single amino acid ketones is reported. The best compound had Ki of 3.5 I~M versus ICE.
Peptidyl aldehydes and ketones have been demonstrated to be potent, reversible inhibitors of the cysteine proteinase interleukin-113 converting enzyme (ICE). 1-5 This novel proteinase has been found to be necessary for the processing of the mature form of the potent cytokine, IL-1~.6-8 ICE-like activities have also been implicated in apoptotic processes in nematodes and neuronal cells.9, lo It has been demonstrated from substrate specificity studies that four amino acids to the N-terminus of the cleavage site are necessary for efficient cleavage of peptides by ICE. 6 However, limitations to the development of peptidyl inhibitors is in part attributed to their physicochemical properties, lack of bioavailability and metabolic instability. 11A2 Therefore, discovery of non-peptidyl small molecule biomimetics remains a primary objective for any therapeutic target. Accordingly, we report herein a novel class of single amino-acid ketones and their evaluation as inhibitors of interleukin-lJ3 converting enzyme.
Truncation of the peptidyl ICE inhibitor AcTyrValAlaAspCO(CH2)4Ph (Ki = 42 nM) 2 to the corresponding single amino acid 1 (AIIoc-AspCO(CHg)4Ph) resulted in total loss of the activity against ICE. It was proposed that more potent inhibitors may result from enhancing the reactivity of the ketone carbonyl of 1 towards the active site cysteine of this enzyme.