<scp>d</scp>-Amino Acid Containing, High-Affinity Inhibitors of Recombinant Human Calpain I

Chatterjee, Sankar; Gu, Zi-Qiang; Dunn, Derek; Tao, Ming; Josef, Kurt A.; Tripathy, Rabindranath; Bihovsky, Ron; Senadhi, Shobha E.; O'Kane, Teresa M.; McKenna, Beth Ann; Mallya, Satish; Ator, Mark A.; Bozyczko–Coyne, Donna; Siman, Robert; Mallamo, John P.

doi:10.1021/jm980035y

Cited by 32 publications

(37 citation statements)

References 17 publications

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“…Aside from the alteration in calpastatin isoforms we found, attenuation of RV dysfunction by MDL-28170 strongly implies a calpain-mediated effect, since that compound is relatively specific for calpain [44]. However, it remains possible that a cysteine protease other than calpain is mechanistically involved in the development of contractile dysfunction and was inhibited by MDL-28170 in this model.…”

Section: Discussionmentioning

confidence: 59%

“…However, it remains possible that a cysteine protease other than calpain is mechanistically involved in the development of contractile dysfunction and was inhibited by MDL-28170 in this model. For example, although MDL-28170 is considered relatively specific for calpain, cathepsin B, a lysosomal cysteine protease, is also inhibited by MDL-28170 at a similar K i of 12-24 nM [44]. We looked for evidence of cathepsin B activation by performing Western immunoblotting for myosin heavy chain [45] using the MF20 antimyosin clone (Developmental Studies Hybridoma Bank, Iowa), but found no differences in myosin heavy chain degradation either (data not shown).…”

Section: Discussionmentioning

confidence: 99%

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Calpain inhibition attenuates right ventricular contractile dysfunction after acute pressure overload

Greyson

Schwartz

et al. 2008

Journal of Molecular and Cellular Cardiology

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Objective-Right ventricular contractile failure from acute RV pressure overload is an important cause of morbidity and mortality, but the mechanism of RV failure in this setting is incompletely defined. We hypothesized that RV dysfunction from acute RV pressure overload is in part due to activation of calpain, and that calpain inhibition would therefore attenuate RV dysfunction.Methods-Anesthetized, open chest pigs were treated with the calpain inhibitor MDL-28170 or with inactive vehicle, and then subjected to acute RV pressure overload for 90 min. RV contractile function was assessed by the regional Frank-Starling relation. RV myocardial tissue was analyzed for evidence of calpain activation and calpain-mediated proteolysis.Results-RV pressure overload caused severe contractile dysfunction, along with significant alterations in the endogenous calpain inhibitor calpastatin typical of calpain activation. MDL-28170 attenuated RV free wall dysfunction by more than 50%. However, there were no differences in degradation of spectrin, desmin, troponin-I or SERCA2 between SHAM operated pigs and pigs subjected to acute RV pressure overload, or between vehicle and MDL-28170 treated pigs.Conclusions-Acute RV pressure overload causes calpain activation, and RV contractile dysfunction from acute RV pressure overload is attenuated by the calpain inhibitor MDL-28170; however, the effect is not explained by inhibition of calpain-mediated degradation of spectrin, desmin, troponin-I or SERCA2. Since this is the first report of any agent that can directly attenuate RV contractile dysfunction in acute RV pressure overload, further investigation of the mechanism of action of MDL-28170 in this setting is warranted.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Calpain inhibition attenuates right ventricular contractile dysfunction after acute pressure overload

Greyson

Schwartz

et al. 2008

Journal of Molecular and Cellular Cardiology

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“…However, recent studies from our laboratory 19 and those of others 20,21 have demonstrated that peptidyl aldehydes with D D-amino acids at the P 2 -position are effective inhibitors of calpain. To further study the significance of the geometry of the P 2 residue on the potency and selectivity of peptidyl calpain inhibitors, we replaced the P 2 a-carbon with a nitrogen atom thus changing the geometry of the P 2 -position from chiral and tetrahedral to achiral and trigonal planar to afford compounds 1-12.…”

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confidence: 94%

A novel series of urea-based peptidomimetic calpain inhibitors

Sanders

Donkor

2006

Bioorganic & Medicinal Chemistry Letters

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“…157 A recent study showed that peptides with D-amino acids at P 2 postion were also potent calpain inhibitors. 158 …”

Section: P 2 Positionmentioning

confidence: 99%

“…Polar pyridineethanol 9 group was used to increase potency and some of pyridineethanol compounds showed a good oral bioavailability. Groups used as N-terminal capping agents 13 are benzyloxycarbonyl, acetyl, aryl (or alkyl) sulfonyl, alkanoyl, substituted benzoyl, naphthoyl, thionaphthalene, 13,160 fluorine, xanthines 13,158 and pyridineethanol, Chromone, …”

Section: N-terminal Cappingmentioning

confidence: 99%

Synthesis of Novel Sulfonamide-Based Calpain Inhibitors and Their Potential as Anti-Tumor Agents

Xu¹

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d-Amino Acid Containing, High-Affinity Inhibitors of Recombinant Human Calpain I

Cited by 32 publications

References 17 publications

Calpain inhibition attenuates right ventricular contractile dysfunction after acute pressure overload

Calpain inhibition attenuates right ventricular contractile dysfunction after acute pressure overload

A novel series of urea-based peptidomimetic calpain inhibitors

Synthesis of Novel Sulfonamide-Based Calpain Inhibitors and Their Potential as Anti-Tumor Agents

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