First Examples of Peptidomimetic Inhibitors of Interleukin-1β Converting Enzyme

Dolle, Roland E.; Prouty, Catherine; Prasad, C. V. C.; Cook, Ewell R.; Saha, Ashis; Ross, Tina Morgan; Salvino, Joseph M.; Helaszek, Carla T.; Ator, Mark A.

doi:10.1021/jm9601516

Cited by 45 publications

(37 citation statements)

References 15 publications

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“…257 Some inhibitors containing these ligands displayed higher potency against caspase-1 than ones with traditional Cbz groups, and some of these substituents increased solubility of the inhibitors. In another approaches Dolle et al used a pyrimidone-scaffold 258 and Golec et al used a pyridone-scaffold for P4 optimization. 278 Recently Galatias et al reported caspase-1 inhibitors containing succinic acid amides as P3-P2 replacements.…”

Section: Caspase Inhibitorsmentioning

confidence: 99%

Small Molecule Active Site Directed Tools for Studying Human Caspases

et al. 2015

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Caspases are proteases of clan CD and were described for the first time more than two decades ago. They play critical roles in the control of regulated cell death pathways including apoptosis and inflammation. Due to their involvement in the development of various diseases like cancer, neurodegenerative diseases or autoimmune disorders, caspases have been intensively investigated as potential drug targets, both in academic and industrial laboratories. This review presents a thorough, deep, and systematic assessment of all technologies developed over the years for the investigation of caspase activity and specificity using substrates and inhibitors, as well as activity based probes, which in recent years have attracted considerable interest due to their usefulness in the investigation of biological functions of this family of enzymes.

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Section: Caspase Inhibitorsmentioning

confidence: 99%

Small Molecule Active Site Directed Tools for Studying Human Caspases

et al. 2015

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“…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]. Laufersweiler et al reported tricyclic pyrrolopyrimidinone dipeptides as ICE inhibitors, many of the analogues exhibited potent ICE inhibition activity with selectivity over Capsase-3 [121].…”

Section: Ice Inhibitorsmentioning

confidence: 99%

Novel Targets for Antiinflammatory and Antiarthritic Agents

Kulkarni

Achaiah²,

Sastry³

2006

CPD

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Inflammation is a complex pathological condition associated with exaggerated human immune system involving various activated immune cells and bio-molecules. Treatment of inflammatory diseases particularly chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease etc. has been a big challenge for scientists as there are no safe drugs available for cure. Current therapeutic approaches to the treatment of inflammatory diseases are centered on cycloxygenase (both COX-1 and 2) proinflammatory enzymes but present available drugs of this category are associated with undesirable gastrointestinal and cardiovascular side effects. Recent scientific advents draw out the secrets of inflammation cache and understanding the involvement of several factors acting as stimulators or inhibitors thus opening new avenues for drug discoveries. Several bio-molecules such as proinflammatory cytokines, components of signal transduction and matrix degrading enzymes resolve inflammatory responses, might be new targets for treatment of chronic inflammatory diseases. This review gathers recent advances in drug research focusing interleukin-1, TNF-alpha, p38 kinase, c-Jun N-terminal kinase MAP kinase, NFkappaB, and matrix metalloproteinases. The biological roles of these inflammatory mediators are clearly understood thus offering new targets for design of novel inhibitors for incurable inflammatory diseases. This also provides an overview of the current nonsteroidal antiinflammatory agents.

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“…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. [3][4][5][6][7][8] These agents incorporate an aspartic acid-derived R-substituted methyl ketone as the essential enzyme recognition element. [3][4][5][6][7][8] These agents incorporate an aspartic acid-derived R-substituted methyl ketone as the essential enzyme recognition element.…”

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confidence: 99%

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

et al. 1997

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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.,

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First Examples of Peptidomimetic Inhibitors of Interleukin-1β Converting Enzyme

Cited by 45 publications

References 15 publications

Small Molecule Active Site Directed Tools for Studying Human Caspases

Small Molecule Active Site Directed Tools for Studying Human Caspases

Novel Targets for Antiinflammatory and Antiarthritic Agents

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

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First Examples of Peptidomimetic Inhibitors of Interleukin-1β Converting Enzyme

Cited by 45 publications

References 15 publications

Small Molecule Active Site Directed Tools for Studying Human Caspases

Small Molecule Active Site Directed Tools for Studying Human Caspases

Novel Targets for Antiinflammatory and Antiarthritic Agents

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

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