Synthesis and evaluation of novel 1-(2-acylhydrazinocarbonyl)-cycloalkyl carboxamides as interleukin-1β converting enzyme (ICE) inhibitors

Soper, David L.; Sheville, Justin; O’Neil, Steven V.; Wang, Yili; Laufersweiler, Michael C.; Oppong, Kofi A.; Wos, John A.; Ellis, Christopher D.; Fancher, Amy N.; Lu, Wei; Suchanek, Maureen K.; Wang, Richard L.; De, Biswanath; Demuth, Thomas P.

doi:10.1016/j.bmcl.2006.05.076

Cited by 5 publications

(6 citation statements)

References 17 publications

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“…This group also displays a high affinity and selectivity toward caspase-1, but still there is no better inhibitor than Pralnacasan 77 among thiazepines peptidomimetics. Another of caspase-1 inhibitors based on the monocyclic scaffold are 1-(2-acylhydrazinocarbonyl)cycloalkylcarboxamides, 178 with their potency depending on the number of atoms building the monocyclic moiety. Cyclohexyloderivatives are preferred over the shorter homologues cyclopentyl, cyclobutyl or cyclopropyl.…”

Section: Caspase Inhibitorsmentioning

confidence: 99%

“…Caspase-1 prefers bulky, hydrophobic residues (tyrosine and tryptophan), , caspase-3 has a near absolute requirement for aspartic acid, , while caspase-8 can accommodate a number of residues, but branched leucine and valine are most preferable. , These different P4 requirements are determined by the size and shape of S4 pocket of particular caspase. The S4 pocket of caspase-1 is large and hydrophobic thus can bind bulky Tyr, Trp, or bicyclic substituents . Caspase-3 binds its substrates or inhibitors in S4 using the Phe250 backbone nitrogen, Asn208 side chain and one water molecule.…”

Section: Caspase Inhibitorsmentioning

confidence: 99%

“…The S4 pocket of caspase-1 is large and hydrophobic thus can bind bulky Tyr, Trp, or bicyclic substituents. 178 Caspase-3 binds its substrates or inhibitors in S4 using the Phe250 backbone nitrogen, Asn208 side chain and one water molecule. Additionally, the carbonyl oxygen from the acetyl group of inhibitors makes an interaction with both hydroxyl group and amide nitrogen of Ser209.…”

Section: Structural Determinants Of Caspases Inhibitionmentioning

confidence: 99%

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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%

Section: Caspase Inhibitorsmentioning

confidence: 99%

Section: Structural Determinants Of Caspases Inhibitionmentioning

confidence: 99%

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Small Molecule Active Site Directed Tools for Studying Human Caspases

et al. 2015

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“…The QSAR study was performed using the previously reported biological activity values (IC 50 nM) (Soper et al, 2006). These values are used as dependent variables.…”

Section: Methodsmentioning

confidence: 99%

QSAR Studies of some New Synthesized Diacylhydrazine Compounds Derived from Indomethacin as Caspase-1 Inhibitors

Al-Naimi¹,

A-Alwahb²,

Hussien³

2018

RJS

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Indomethacin (1) reacts with absolute ethanol in presence of conc. sulphuric acid to form the ester (2). This ester was converted into the hydrazide (3) by treatment with hydrazine hydrate. The reaction of the hydrazide (3) with acid chlorides (of indomethacine, dichlofenac, mefenamic acid, aspirin and ibuprofen) in dry xylene afforded the N,N'-diacylhydrazine compounds (4-8). A series of new 2,5-disubstituted-1,3,4-oxadiazoles (9-13) derived from indomethacin (1) was obtained by the dehydrative cyclization of the corresponding N,N'-diacylhydrazines(4-8), in presence of an excess of thionyl chloride. The quantitative structure-activity relationship (QSAR) analysis of the synthesized compounds was also performed to compute the parameters that affect the biological activity (inhibitory activity IC 50). Docking analysis was also performed to predict the interactions between the synthesized compounds with Caspase-1 (Interleukin-1 converting enzyme). The study is aimed to predict factor affecting the biological activity of the prepared compounds by employing the QSAR analysis. The structures of the synthesized compounds were confirmed by the spectroscopic methods.

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“…These include urazolopyrazine-based "-strand peptidomimeticsdesigned as inhibitors for caspase-3 and caspase-8, [72] hydantoin-based peptidomimetics as inhibitors of caspase-3 [73], dipeptidylaspartylfluormethylketones with unnatural amino acids [74], 1-(2-acylhydrazinocarbonyl)-cycloalkyl carboxamides, [75] 8,5-fused bicyclic compounds, [76] and peptidomimetics containing a caprolactam ring [77].…”

Section: Active Site Inhibitorsmentioning

confidence: 99%

Caspases – Key Players in Apoptosis

Cade

Clark

2015

Proteases in Apoptosis: Pathways, Protocols and Translational Advances

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Caspases are the terminal proteases involved in apoptosis, as well as being involved in inflammation. The apoptotic caspases can be classified as either initiator or effector caspases based on both their position in the caspase cascade and their activation mechanism. Initiator caspases require dimerization to be activated, and cleavage of a loop called the intersubunit linker stabilizes the active enzyme. Effector caspases, on the other hand, are found as dimers in the cell and cleavage of the intersubunit linker is the key step in their activation.The name caspase is short for cysteinyl aspartate-specific protease. As their name suggests, these enzymes hydrolyze peptide bonds after certain aspartate residues using a catalytic cysteine (with the aid of an active-site histidine residue). Caspases can be inhibited by endogenous inhibitors such as XIAP, by synthetic inhibitors which target either the active site or an allosteric site, or by post-translational modification. Further research is needed to find novel activators and inhibitors of caspases to treat diseases which involve misregulation of apoptosis.

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Synthesis and evaluation of novel 1-(2-acylhydrazinocarbonyl)-cycloalkyl carboxamides as interleukin-1β converting enzyme (ICE) inhibitors

Cited by 5 publications

References 17 publications

Small Molecule Active Site Directed Tools for Studying Human Caspases

Small Molecule Active Site Directed Tools for Studying Human Caspases

QSAR Studies of some New Synthesized Diacylhydrazine Compounds Derived from Indomethacin as Caspase-1 Inhibitors

Caspases – Key Players in Apoptosis

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