- Design, synthesis, and structure–activity relationship study of epoxysuccinyl–peptide derivatives as cathepsin B inhibitors
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Cathepsin B is a lysosomal cysteine protease involved in many diseases. The present research demonstrates that derivatives of epoxysuccinyl–peptide are effective and selective cathepsin B inhibitors. We synthesized a series of epoxysuccinyl–peptide deriva
- Zhang, Xiaoye,Yang, Xiaohong,Wang, Hongqiang,Li, Song,Guo, Kun,Jiang, Dan,Xiao, Junhai,Liang, Di
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Read Online
- 2,3-EPOXY SUCCINYL DERIVATIVE, PREPARATION METHOD THEREFOR, AND USES THEREOF
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The present invention relates to a 2,3-epoxy succinyl derivative, a preparation method and a use thereof, in particular, the present invention relates to a compound represented by Formula (1), a racemate or an optical isomer thereof, a solvate thereof, or
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Paragraph 0223; 0224
(2019/01/17)
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- Cysteine protease inhibitors and uses thereof
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The invention provides for novel cysteine protease inhibitors and compositions comprising novel cysteine protease derivatives. The invention further provides for methods for treatment of neurodegenerative diseases comprising administration novel cysteine
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Page/Page column 39
(2016/08/29)
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- Design, synthesis, and screen of cathepsin K inhibitors
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We synthesized a series of epoxysuccinic acid derivatives and evaluated their in vitro cathepsin K inhibitory activity The screening results show that the potency of compounds 9e, 9d, 9p, 9j and 9k (IC50 ≤ 0.005 μmol/L) were equal to or greater than that of the lead compound 9a. Less hydrophobic compounds showed weaker potency, which can be explained by the hydrophobic nature of the cathepsin K binding pockets.
- Yu, Ying-Ying,Sun, Wei,Dong, Lei,Liu, Hai-Dong,Jiang, Dan,Xiao, Jun-Hai,Yang, Xiao-Hong,Li, Song
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p. 715 - 718
(2013/07/26)
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- Design, synthesis, and optimization of novel epoxide incorporating peptidomimetics as selective calpain inhibitors
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Hyperactivation of the calcium-dependent cysteine protease calpain 1 (Cal1) is implicated as a primary or secondary pathological event in a wide range of illnesses and in neurodegenerative states, including Alzheimer's disease (AD). E-64 is an epoxide-containing natural product identified as a potent nonselective, calpain inhibitor, with demonstrated efficacy in animal models of AD. By use of E-64 as a lead, three successive generations of calpain inhibitors were developed using computationally assisted design to increase selectivity for Cal1. First generation analogues were potent inhibitors, effecting covalent modification of recombinant Cal1 catalytic domain (Cal1cat), demonstrated using LC-MS/MS. Refinement yielded second generation inhibitors with improved selectivity. Further library expansion and ligand refinement gave three Cal1 inhibitors, one of which was designed as an activity-based protein profiling probe. These were determined to be irreversible and selective inhibitors by kinetics studies comparing full length Cal1 with the general cysteine protease papain.
- Schiefer, Isaac T.,Tapadar, Subhasish,Litosh, Vladislav,Siklos, Marton,Scism, Rob,Wijewickrama, Gihani T.,Chandrasena, Esala P.,Sinha, Vaishali,Tavassoli, Ehsan,Brunsteiner, Michael,Fa', Mauro,Arancio, Ottavio,Petukhov, Pavel,Thatcher, Gregory R. J.
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supporting information
p. 6054 - 6068
(2013/09/02)
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- Two-step labeling of endogenous enzymatic activities by Diels-Alder ligation
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A ligation strategy based on the Diels-Alder [4+2] cycloaddition for the two-step activity-based labeling of endogenously expressed enzymes in complex biological samples has been developed. A panel of four diene-derivatized proteasome probes was synthesized, along with a dienophile-functionalized BODIPY(TMR) tag. These probes were applied in a Diels-Alder labeling procedure that enabled us to label active proteasome β-subunits selectively in cellular extracts and in living cells. We were also able to label the activity of cysteine proteases in cell extracts by utilizing a diene-derivatized cathepsin probe. Importantly, the Diels-Alder strategy described here is fully orthogonal with respect to the Staudinger-Bertozzi ligation, as demonstrated by the independent labeling of different proteolytic activities by the two methods in a single experiment.
- Willems, Lianne I.,Verdoes, Martijn,Florea, Bogdan I.,Van Der Marel, Gijsbert A.,Overkleeft, Herman S.
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p. 1769 - 1781
(2011/04/18)
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- Novel irreversible epidermal growth factor receptor inhibitors by chemical modulation of the cysteine-trap portion
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Irreversible EGFR inhibitors can circumvent acquired resistance to first-generation reversible, ATPcompetitive inhibitors in the treatment of non-small-cell lung cancer. They contain both a driver group, which assures target recognition, and a warhead, generally an acrylamide or propargylamide fragment that binds covalently to Cys797 within the kinase domain of EGFR. We performed a systematic exploration of the role for the warhead group, introducing different cysteine-trapping fragments at position 6 of a traditional 4-anilinoquinazoline scaffold. We found that different reactive groups, including epoxyamides (compounds 3-6) and phenoxyacetamides (compounds 7-9), were able to irreversibly inhibit EGFR. In particular, at significant lower concentrations than gefitinib (1), (2R,3R)N-(4-(3-bromoanilino)quinazolin-6-yl)- 3 -(piperidin-1 -ylmethyl)oxirane-2-carboxamide (6) inhibited EGFR autophosphorylation and downstream signaling pathways, suppressed proliferation, and induced apoptosis in gefitinib-resistant NSCLC H1975 cells, harboring the T790M mutation in EGFR.
- Carmi, Caterina,Cavazzoni, Andrea,Vezzosi, Stefano,Bordi, Fabrizio,Vacondio, Federica,Silva, Claudia,Rivara, Silvia,Lodola, Alessio,Alfieri, Roberta R.,La Monica, Silvia,Galetti, Maricla,Ardizzoni, Andrea,Petronini, Pier Giorgio,Mor, Marco
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scheme or table
p. 2038 - 2050
(2010/08/20)
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- Aza-peptidyl michael acceptor and epoxide inhibitors - Potent and selective inhibitors of Schistosoma mansoni and Ixodes ricinus legumains (asparaginyl endopeptidases)
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Aza-peptide Michael acceptors and epoxides with the general structure of YCO-Ala-Ala-AAsn-trans-CH=CHCOR and YCO-Ala-Ala-AAsn-EP-COR, respectively, are shown to be potent inhibitors of asparaginyl endopeptidases (legumains) from the bloodfluke, Schistosoma mansoni (SmAE), and the hard tick, Ixodes ricinus (IrAE). Structure-activity relationships (SARs) were determined for a set of 41 aza-peptide Michael acceptors and eight aza-peptide epoxides. Both enzymes prefer disubstituted amides to monosubstituted amides in the P10 position, and potency increased as we increased the hydrophobicity of the inhibitor in this position. Extending the inhibitor to P5 resulted in increased potency, especially against IrAE, and both enzymes prefer small over large hydrophobic residues at P2. Aza-peptide Michael acceptor inhibitors are more potent than aza-peptide epoxide inhibitors, and for some of these compounds, second-order inhibiton rate constants are the fastest yet discovered. Given the central functions of these enzymes in both parasites, the data presented here may facilitate the eventual design of selective antiparasitic drugs.
- Ovat, Asli,Muindi, Fanuel,Fagan, Crystal,Brouner, Michelle,Hansell, Elizabeth,Dvo?ák, Jan,Sojka, Daniel,Kopá?ek, Petr,McKerrow, James H.,Caffrey, Conor R.,Powers, James C.
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experimental part
p. 7192 - 7210
(2010/07/05)
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- NOVEL DRUGS FOR DEMENTIA
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The invention is directed to compounds that are prodrugs containing a chemical delivery system (CDS) moiety and a cysteine protease inhibitor moiety. The CDS moiety targets the prodrug to the brain or central nervous system. The cysteine protease inhibitor inhibits cysteine proteases upon release from the prodrug. Cysteine protease inhibitors are effective for treating dementia, Alzheimer's disease and vascular dementia. Targeting the brain or central nervous system offers significant advantages in treating these conditions and diseases. A preferred CDS prodrug is a dihydrotrigoneline CDS moiety coupled to an epoxysuccinyl peptide cysteine protease inhibitor moiety.
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- An improved preparation of the activity-based probe JPM-OEt and in situ applications
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A short, stereoselective synthesis of the general, cell permeable cathepsin probe JPM-OEt, is presented. The synthetic route is improved and described in more detail than previous reports for related compounds. This serves as a facile method for the synth
- Chehade, Kareem A. H.,Baruch, Amos,Verhelst, Steven H. L.,Bogyo, Matthew
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p. 240 - 244
(2007/10/03)
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- Configuration and enantioselective synthesis of the fungal metabolite WF14861
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A short enantioselective synthesis of the cathepsine inhibitor WF14861 (1) from the funghi Colletotrichum sp. as well as of its diasteroisomer 21 is presented. Comparison of the NMR data of the final products and, in particular, of the [α]D values of the intermediates allowed the confirmation of the formerly proposed structure 1. In addition, the so far unknown absolute configuration of all three stereogenic centres of WF14861 could be established by this synthesis.
- Detterbeck, Richard,Hesse, Manfred
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p. 222 - 232
(2007/10/03)
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- EPOXYSUCCINIC ACID DERIVATIVES, THEIR PRODUCTION AND USE
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The present invention relates to a compound of the formula: STR1 wherein R 1 stands for an optionally esterified or amidated carboxyl group, X stands for an optionally substituted divalent hydrocarbon residue, R 2 stands for hydrogen or an optionally subs
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- EPOXYSUCCINIC ACID DERIVATIVES
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A compound of the general formula: STR1 wherein R 1 represents a carboxyl group which may optionally be esterified or amidated; R 2 represents a cyclic group which may optionally be substituted or a polar group; n is an integer of 0 to 6; R 3 represents hydrogen or a hydrocarbon residue which may optionally be substituted; R 4 represents (1) a hydrocarbon residue which is substituted by an optionally protected amino group or (2) an alkenyl group; or R 3 and R 4 may be combined with the adjacent nitrogen atom to form a heterocyclic group containing at least two hetero atoms, or a salt thereof.The compound or a salt thereof of the present invention inhibits thiol proteases such as cathepsin L and B and serves well as a prophylactic/therapeutic agent for bone diseases such as osteoporosis.
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- Mechanistic studies on the inactivation of papain by epoxysuccinyl inhibitors
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Analogs of the epoxysuccinyl peptide cysteine proteinase inhibitor, EP- 475 (2a), in which the free carboxylate has been replaced by hydroxamic acid, amide, methyl ketone, hydroxyl, and ethyl ester functionalities, have been synthesized. Individual rate c
- Meara, Joseph P.,Rich, Daniel H.
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p. 3357 - 3366
(2007/10/03)
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- E-64 analogs as inhibitors of cathepsin L and cathepsin S: Importance of the S2-P2 interactions for potency and selectivity
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A number of epoxysuccinyl amino acid benzyl esters (HO-Eps-AA-OBzl, 1) in which the amino acid (AA) had been systematically varied were tested as inhibitors of cathepsins L and S. These E-64 analogs were designed to investigate whether selectivity for cat
- Gour-Salin,Goursalin,Lachance,Bonneau,Storer,Kirschke,Broemme
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p. 227 - 241
(2007/10/02)
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