Peptidomimetic aminomethylene ketone inhibitors of interleukin-1β-converting enzyme (ICE)

Semple, Graeme; Ashworth, Doreen M.; Batt, Andrzej R.; Baxter, Andrew; Benzies, D. W. M.; Elliot, L. H.; Evans, Declan; Franklin, Richard J.; Hudson, Peter; Jenkins, Paul D.; Pitt, Gary R. W.; Rooker, David P.; Yamamoto, Satoshi; Isomura, Yasuo

doi:10.1016/s0960-894x(98)00136-x

Cited by 31 publications

(13 citation statements)

References 8 publications

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“…258 There are additional reports describing the utility of pyrimidone (or pyridone) moiety for mimicking the P3-P2 region. 278–280 Pyrimidone and pyridone groups were substituted with different ligands to explore the S2 active site pocket of caspase-1. This new scaffold significantly reduced peptidic character, but also decreased the inhibitory potency toward caspase-1.…”

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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“…Among the most potent peptidomimetic ICE inhibitors are derivatives in which the ValHis residues of the substrate P1-P4 cleavage sequence have been replaced with a pyridone or pyrimidone scaffold (Table LXII). [137][138][139][140] This strategy has been adopted from the successful use of pyridones as ValPro mimetics in the design of inhibitors of human leukocyte elastase. 141 While the primary purpose of the pyridone/pyrimidone scaffold is to maintain the crucial hydrogen bonding pattern along the ''peptide'' backbone, it was also found that substituents at the 6 position of the pyridone ring led to increased potency against ICE by filling the lipophilic S2 pocket (4-72 vs. 4-71).…”

Section: B Interleukin-1 Converting Enzyme (Ice) Inhibitorsmentioning

confidence: 99%

Small molecular anti-cytokine agents

2005

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The recent successful introduction of the anti-cytokine biologicals Etanercept, Infliximab, Adalimumab, and Anakinra has stimulated the search for anti-cytokine small-molecules. A number of molecular targets have been identified for the development of such small molecular anti-cytokine agents. The focus of this review will be on those inhibitors of cytokine production, which target either p38 mitogen activated protein (MAP) kinase, TNF-alpha converting enzyme (TACE), or IL-1beta converting enzyme (ICE). P38 MAP kinase occupies a central role in the signaling network responsible for the upregulation of proinflammatory cytokines like interleukin 1beta (IL-1beta) and TNF-alpha, and regulates their biosynthesis at both the transcriptional and translational level. TACE and ICE are two proteases required for the processing of proTNF-alpha and proIL-1beta, respectively into their mature, proinflammatory form. Since the mid-1990s, a plethora of inhibitors of p38 MAP kinase, TACE, and ICE has been characterized in vitro, and individual representatives from all three inhibitor classes have in the meantime been advanced into clinical trials. This review will highlight the correlation between effective inhibition at the molecular target and cellular activity in functional assays of cytokine, particularly TNF-alpha and IL-1beta, production. Structure-activity relationships (SAR) will be discussed regarding activity at the respective enzyme target, but also with regard to properties required for efficient in vitro and in vivo cellular activity (e.g., oral availability, solubility, cell penetration, etc.).

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“…A large number of representatives of N -acyl-α-amino acids have anticancer (e.g., methotrexate) [ 17 ], mucolytic (e.g., N -acetyl cysteine) [ 18 ], antihypertensive (e.g., angiotensin-converting enzyme inhibitors: captopril, enalapril, lisinopril) [ 19 ], antianemic (e.g., folic acid) [ 20 ], anti-ulcer (e.g., benzotript) [ 21 ] effects, and are specific antidotes in acute intoxications [ 22 , 23 ]. The N -acyl-α-amino ketones display antiviral (e.g., rupintrivir) [ 24 ], anti-inflammatory [ 25 ], and antithrombotic [ 26 ] actions.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of New N-Acyl-α-amino Ketones and 1,3-Oxazoles Derivatives

et al. 2021

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In order to develop novel bioactive substances with potent activities, some new valine-derived compounds incorporating a 4-(phenylsulfonyl)phenyl fragment, namely, acyclic precursors from N-acyl-α-amino acids and N-acyl-α-amino ketones classes, and heterocycles from the large family of 1,3-oxazole-based compounds, were synthesized. The structures of the new compounds were established using elemental analysis and spectral (UV-Vis, FT-IR, MS, NMR) data, and their purity was checked by reversed-phase HPLC. The newly synthesized compounds were evaluated for their antimicrobial and antibiofilm activities, for toxicity on D. magna, and by in silico studies regarding their potential mechanism of action and toxicity. The 2-aza-3-isopropyl-1-[4-(phenylsulfonyl)phenyl]-1,4-butanedione 4b bearing a p-tolyl group in 4-position exhibited the best antibacterial activity against the planktonic growth of both Gram-positive and Gram-negative strains, while the N-acyl-α-amino acid 2 and 1,3-oxazol-5(4H)-one 3 inhibited the Enterococcus faecium biofilms. Despite not all newly synthesized compounds showing significant biological activity, the general scaffold allows several future optimizations for obtaining better novel antimicrobial agents by the introduction of various substituents on the phenyl moiety at position 5 of the 1,3-oxazole nucleus.

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Peptidomimetic aminomethylene ketone inhibitors of interleukin-1β-converting enzyme (ICE)

Cited by 31 publications

References 8 publications

Small Molecule Active Site Directed Tools for Studying Human Caspases

Small Molecule Active Site Directed Tools for Studying Human Caspases

Small molecular anti-cytokine agents

Synthesis and Biological Evaluation of New N-Acyl-α-amino Ketones and 1,3-Oxazoles Derivatives

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