PYRIDONE-BASED PEPTIDOMIMETIC INHIBITORS OF INTERLEUKIN-1β-CONVERTING ENZYME (ICE)

Semple, Graeme; Ashworth, Doreen M.; Baker, Graham R.; 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.; Sheppard, Andrew; Szelke, M.; Yamamoto, Satoshi; Isomura, Yasuo

doi:10.1016/s0960-894x(97)00220-5

Cited by 30 publications

(12 citation statements)

References 10 publications

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“…Several adaptations have been made to these reversible and irreversible inhibitors to improve cell penetration and stability allowing for the development of effective therapeutics. A number of P2 and P3 replacements have been developed; mainly pyridone, pyrimidone and pyridazinodiazepine scaffolds [70, 71]. Non‐pep‐tide caspase inhibitors are also currently in development.…”

Section: Small Molecule Inhibitors Of Caspase Activity and Activationmentioning

confidence: 99%

Caspases as therapeutic targets

Howley

Fearnhead

2008

J Cellular Molecular Medi

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The development of small molecules to modulate caspase activity offers a novel therapeutic strategy in the treatment of apoptosis-related and inflammatory diseases. Caspases are key mediators of apoptosis and inflammation; deregulation of their activation or expression can lead to the development of conditions such as neurodegenerative and autoinflammatory disorders. This review details the different caspase-associated disorders while focusing on caspase-1 inhibition as a potential therapeutic strategy. Problems facing the development of effective and safe caspase therapeutics will also be addressed.

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Section: Small Molecule Inhibitors Of Caspase Activity and Activationmentioning

confidence: 99%

Caspases as therapeutic targets

Howley

Fearnhead

2008

J Cellular Molecular Medi

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“…A benzyl substituent from the 6-position of the pyridone ring ( 18 ) optimally accesses the S 2 subsite, but a variety of alkyl or aromatic substitutions from the P 2 glycine yielded more effective compounds ( 19 ). Pyrimidone mimetics ( 20 ) were slightly less active than the equivalent pyridones …”

Section: Caspase Inhibitor Discoverymentioning

confidence: 99%

“…N-Methylated peptide inhibitors demonstrated that only the P 1 and P 3 amide nitrogens were essential for inhibitory action, 274,277 and crystallography showed that the P 3 carbonyl oxygen participates in a hydrogen bond with the enzyme. Glycylaminopyridones (18) 278,279 that accommodate this pattern bind adequately. A benzyl substituent from the 6-position of the pyridone ring (18) optimally accesses the S 2 subsite, but a variety of alkyl or aromatic substitutions from the P 2 glycine yielded more effective compounds (19).…”

Section: Figurementioning

confidence: 99%

Caspases as Targets for Anti-Inflammatory and Anti-Apoptotic Drug Discovery

2000

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Cloning of caspase-1 through -10 and -13 is reviewed in ref 2; a human caspase-14 sequence is reported in ref 3. b Single amino acid codes are given for preferred residues at the P4 substrate position and represent consensus between combinatorial and defined peptide specificity studies. 43,42 For some, two similarly preferred amino acids are listed. c Caspase-3, -6, -7, and -13 have pro-domains of 40 amino acids or less; in contrast, the pro-domains of the other caspases are >100 residues. d Proposed role based on homologies to better-understood caspases. e Catalytic activity for caspase-14 has not been demonstrated. f Caspase-6 can also directly activate caspase-3 and possibly -7 and so can be considered to have both effector and signaling roles. 288

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“…Biphenyl acetic acids and derivatives were found to have immense potential in drug discovery research, as an example, either useful as agents for treatment or prevention of various epileptic seizures or tissue factor VIIa inhibitors . 2-Pyridone is found to be a core structure of a wide range of biologically important compounds, such as ICE inhibitor (interleukin-1B), wherein 2-pyridone has been incorporated as a dipeptido mimic, as CB2 agonists . The 2-pyridone group has been used as a ligand for olefination of arenes as well …”

Section: Introductionmentioning

confidence: 99%

Additive-Free, Pd-Catalyzed 3-Amino-1-methyl-1H-pyridin-2-one-Directed C(sp²)–H Arylation and Methylation in Water

2019

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Small molecules containing a 2-pyridone unit received much attention due to their significance in medicinal chemistry. In this regard, development of novel methodologies via metal-catalyzed carbon–carbon bond formation by chelation-assisted C–H activation will be an attractive method to achieve therapeutically important 2-pyridone analogues and arylated acid synthons. We report our studies on a Pd(II)-catalyzed coupling reaction between methyl, aryl, heteroaryl iodides, and sp2 carbons both at β- and γ-positions using 3-amino-1-methyl-1H-pyridin-2-one as an efficient, built-in bidentate N,O-directing group (DG) toward the synthesis of pyridone derivatives. The effect of temperature, solvent, reagent equivalence, and substrate has been investigated for this DG-mediated late-stage functionalization reactions along with the crystal structure of a selected analogue. Moreover, this DG has been successfully applied for ortho-selective C(sp2)–H activation in aqueous medium in high yields to demonstrate the practicability of this present methodology.

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PYRIDONE-BASED PEPTIDOMIMETIC INHIBITORS OF INTERLEUKIN-1β-CONVERTING ENZYME (ICE)

Cited by 30 publications

References 10 publications

Caspases as therapeutic targets

Caspases as therapeutic targets

Caspases as Targets for Anti-Inflammatory and Anti-Apoptotic Drug Discovery

Additive-Free, Pd-Catalyzed 3-Amino-1-methyl-1H-pyridin-2-one-Directed C(sp²)–H Arylation and Methylation in Water

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PYRIDONE-BASED PEPTIDOMIMETIC INHIBITORS OF INTERLEUKIN-1β-CONVERTING ENZYME (ICE)

Cited by 30 publications

References 10 publications

Caspases as therapeutic targets

Caspases as therapeutic targets

Caspases as Targets for Anti-Inflammatory and Anti-Apoptotic Drug Discovery

Additive-Free, Pd-Catalyzed 3-Amino-1-methyl-1H-pyridin-2-one-Directed C(sp2)–H Arylation and Methylation in Water

Contact Info

Product

Resources

About

Additive-Free, Pd-Catalyzed 3-Amino-1-methyl-1H-pyridin-2-one-Directed C(sp²)–H Arylation and Methylation in Water