Oxamyl dipeptide caspase inhibitors developed for the treatment of stroke

Linton, Steven D.; Aja, Teresa; Allegrini, Peter R.; Deckwerth, Thomas L.; Díaz, José-Luis; Hengerer, Bastian; Herrmann, Julia; Jahangiri, Kathy G.; Kallen, Joerg; Karanewsky, Donald S.; Meduna, Steven P.; Nalley, Kip; Robinson, Edward D.; Roggo, Silvio; Rovelli, Giorgio; Sauter, André; Sayers, Robert O.; Schmitz, A.; Smidt, Robert; Ternansky, Robert J.; Tomaselli, Kevin J.; Ullman, Brett R.; Wiessner, Christoph; Wu, Joe C.

doi:10.1016/j.bmcl.2003.12.106

Cited by 23 publications

(16 citation statements)

References 26 publications

(3 reference statements)

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“…In Table 25 we collected some examples of 1-Naphthyl-CO-Val-Asp-based inhibitors. The same group have also used oxamyl dipeptides to investigate P1′ 298 (Table 26). SAR studies led to the discovery of new group of caspase inhibitors with improved cellular potency compared to the previously reported 1-Naphthyl-CO-Val-Asp derivatives.…”

Section: Caspase Inhibitorsmentioning

confidence: 99%

“…Shortly thereafter Linton et al used oxamyl dipeptides for SAR studies directed toward P1′, P2 and P4 regions. 298 Almost 50 compounds with diverse P4 were synthesized and tested toward murine caspase-1, human caspases −3, −6, and −8 and also used in four cellular assays (Jurkat, THP-1, Con A and SKW 6.4). This study demonstrated that many different substituents are tolerated in P4.…”

Section: Caspase Inhibitorsmentioning

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%

Small Molecule Active Site Directed Tools for Studying Human Caspases

et al. 2015

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“…Possible mechanisms of caspase-3 inhibition have been studied for a large variety of compounds possessing the electrophilic carbonyls, such as peptidealdehydes [13,14], isatins [15], peptidyl ketones [16,17], homophthalimides [18] and quinazolinones [19]. In the reported cases, the mechanism involved addition of the enzyme's catalytic cysteine residue to carbonyl moiety.…”

Section: Biological Evaluationmentioning

confidence: 98%

Pyrrolo[3,4-c]Quinoline-1,3-Diones as Potent Caspase-3 Inhibitors: Synthesis and SAR of 8-Sulfamoyl-1,3-Dioxo-2,3-Dihydro-1H-Pyrrolo[3,4- c]Quinolines

Кравченко¹,

Kuzovkova²,

Kysil³

et al. 2006

LDDD

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Synthesis, biological evaluation and structure-activity relationships for a series of 8-sulfamoyl-1,3-dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines are described. These compounds represent a new chemotype of nonpeptide small molecule inhibitors of caspase-3. Among the studied compounds, several potent inhibitors have been identified. The most active compounds within this series inhibited caspase-3 with IC 50 in the range of 23-30 nM.

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“…They developed C-DEVD-H, a conformationally constrained peptidomimetic caspase inhibitor, serving as a lead for the further development of acyl dipeptide compounds [45][46][47]. Idun recently designed potent caspase inhibitors based on oxamyl dipeptides [48]. As electrophilic warheads polyfluorophenoxy, dichlorobenzoyloxy or diphenylphosphinyl derivates gave the best results.…”

Section: Pharmacological Approaches Of Caspase Inhibitionmentioning

confidence: 99%

Pharmacological Modulation of Caspase Activation

Fischer¹,

Schulze‐Osthoff

2005

CMCAIAA

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Deregulation of apoptosis resulting either in inappropriate loss or accumulation of cells is a major cause of many severe pathological conditions such as cancer, autoimmune diseases, microbial infections and degenerative disorders. Consequently, great interest has emerged in devising therapeutic strategies for intervening with cell death, either in a pro-or antiapoptotic direction. Among the different apoptosis-based drug targets, caspases, a family of intracellular cysteine proteases are most promising candidates, because they form the central core of the apoptotic machinery that coordinate cell death from various signals. Inappropriate cell death can be efficiently blocked by caspase inhibitors, whereas caspase activation or the inhibition of endogenous caspase inhibitors might be useful for the eradication of unwanted cells. Currently, numerous novel approaches are being followed employing gene therapy, antisense strategies, recombinant biologics or organic chemistry in order to target caspases or their endogenous inhibitors. Exciting proof-of-principle evidence obtained in several animal models confirms the validity of strategies targeting caspases and their enormous therapeutic potential. Although mostly in preclinical state, several therapeutics have recently progressed to clinical testing or were even approved by drug administration. This review summarizes the recent advances in the field of caspase targeting and discusses its wide-ranging opportunities for different human diseases.

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Oxamyl dipeptide caspase inhibitors developed for the treatment of stroke

Cited by 23 publications

References 26 publications

Small Molecule Active Site Directed Tools for Studying Human Caspases

Small Molecule Active Site Directed Tools for Studying Human Caspases

Pyrrolo[3,4-c]Quinoline-1,3-Diones as Potent Caspase-3 Inhibitors: Synthesis and SAR of 8-Sulfamoyl-1,3-Dioxo-2,3-Dihydro-1H-Pyrrolo[3,4- c]Quinolines

Pharmacological Modulation of Caspase Activation

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