Pyridazinodiazepines as a High-Affinity, P₂−P₃Peptidomimetic Class of Interleukin-1β-Converting Enzyme Inhibitor

Abstract

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.,

Caspase Inhibitors: A Pharmaceutical Industry Perspective

“…(9)) [74]. Replacement of the P2 backbone nitrogen with an oxygen was in agreement with previous work [25] and structural information regarding the active sites of caspases [75]. Results of testing in the Fas-liver model showed that the efficacy of MX1153 is short-lived, and high doses are required for long lasting protection.…”

“…Working from a patent estate licensed from SanofiWinthrop [24][25][26], they developed a series of pyridazinodazepine inhibitors in the context of a collaboration with Aventis, resulting in HMR3480/VX-740, or pralnacasan [27][28][29][30][31][32] (Fig. (2)).…”

“…These irreversible inhibitors were more potent in apoptotic cellular assays, and overall more potent pan caspase inhibitors. Examples of these analogues are shown in Table 6, compounds (22)(23)(24)(25).…”

Novel Targets for Antiinflammatory and Antiarthritic Agents

“…Some of methylene ketones are modified for improved P1 binding with enzyme [115][116][117]. Some of peptides were designed as constrained dipeptides [118]. Many reports have been published on nonpeptidomemetic ICE inhibitors containing pyridinone or pyrimidone scaffolds [119,120].…”

Tailoring Peptidomimetics for Targeting Protein–Protein Interactions

“…Modifications which enable the classification of type I as peptidomimetics are the ones made at the amide backbone structure (e.g., amide bond isosteres). Type I mimetics have been used as inhibitors for aspartic proteases (74), cysteine protease (75), renin (76,77), and the critical p53/MDM2 interaction present in many cancers (78).…”