Interleukin-1 -converting enzyme (ICE) is the obligate enzyme for processing biologically inactive pro IL-1 to the biologically active cytokine, IL-1 . 1 Since this original discovery, the biological role of the enzyme has broadened to include the regulation of certain apoptotic processes, and a large family of homologs has been identified. 2 In a series of communications, we have chronicled our research efforts on the discovery of potent, selective, irreversible inhibitors of ICE. 3-8 These agents incorporate an aspartic acid-derived R-substituted methyl ketone as the essential enzyme recognition element. 7 The highest rates of inactivation, hence greatest potency, are observed in the tripeptide series i. Most recently, we disclosed the first examples of peptidomimetic inhibitors ii of the enzyme in which the Val-Ala unit (P 3 -P 2 residues) was replaced by a pyrimidineacetic acid surrogate. 6 In this final communication, we describe the pyridazinodiazepines iii as a new peptidomimetic class of ICE inhibitor displaying exceptionally high affinity for the enzyme.Previously, we documented the hydrogen-bonding pattern between ICE and its peptide-based inhibitors i by conducting an N-methyl scan of the tripeptide backbone. 4 These results demonstrated that the P 1 and P 3 amido hydrogens were required for high-affinity binding, leading to the replacement of P 3 -P 2 residues in i with a pyrimidine acetyl mimetic 6,9 as in ii. Although the provision for correct hydrogen bonding exists in ii, the potency in this class did not strictly coincide with that of the tripeptide. For example in the tripeptide series, increased rates of inactivation are observed upon exchange of the N-terminal benzyloxycarbonyl (1: R ) Z) to the 4-(methylthio)benzoyl group † Present address: Pharmacopeia, Inc.,
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.