- COMPOSITIONS AND METHODS FOR SYNTHESIZING (2S,3S)-TRANS-EPOXYSUCCINYL-L-LEUCYL-AMIDO-3-METHYLBUTANE ETHYL ESTER
-
In alternative embodiments the invention provides methods for synthesizing AB-007 (also called loxistatin, E64d, EST or ((2S,3S)-trans-epoxysuccinyl-L-leucyl-amido-3-methylbutane ethyl ester) and its acid form E64c (loxistatin acid), and various synthetic
- -
-
Paragraph 0056; 0059; 0066; 0067; 0110; 0111
(2017/07/06)
-
- Additivity or cooperativity: Which model can predict the influence of simultaneous incorporation of two or more functionalities in a ligand molecule?
-
Predicting how binding affinity responds to ligand structural modifications in structure-activity relationship studies (SAR) is a major challenge in medicinal chemistry. This is particularly true when two or more of these modifications are carried out simultaneously. In this study, we present binding affinity data from several series of thermolysin inhibitors in which simultaneous structural modifications were investigated to determine whether they are cooperative or additive. Data revealed that, while additivity is at work in some cases, cooperativity is more commonly demonstrated. Cooperativity and additivity were then correlated with ligand descriptors, such as the spacing and the topological features of the modified groups, in a manner that may provide guidance as to when each model should be utilized. Cooperativity was particularly associated with contiguous groups and small unbranched hydrophobic side chain. Additivity, on the other hand, was associated with moderately distant hydrophobic group combinations and side chain branching. Such correlations can improve the predictability of SAR studies and can provide a starting point for additional investigations that may lead to further significant enhancements in the current scoring functions.
- Nasief, Nader N.,Hangauer, David
-
p. 897 - 915
(2015/05/27)
-
- Influence of neighboring groups on the thermodynamics of hydrophobic binding: An added complex facet to the hydrophobic effect
-
The thermodynamic consequences of systematic modifications in a ligand side chain that binds in a shallow hydrophobic pocket, in the presence and absence of a neighboring ligand carboxylate group, were evaluated using isothermal titration calorimetry (ITC
- Nasief, Nader N.,Hangauer, David
-
supporting information
p. 2315 - 2333
(2014/04/17)
-
- Design, synthesis, and screen of cathepsin K inhibitors
-
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
-
p. 715 - 718
(2013/07/26)
-
- Design, synthesis and evaluation of 3-methylene-substituted indolinones as antimalarials
-
The design, synthesis and evaluation of 3-methylene-substituted indolinones as falcipain inhibitors and antiplasmodial agents are described. These compounds react readily with thiols via an addition-elimination mechanism, indicating their potential as cys
- Praveen Kumar,Gut, Jiri,Guedes, Rita C.,Rosenthal, Philip J.,Santos, Maria M.M.,Moreira, Rui
-
experimental part
p. 927 - 933
(2011/04/16)
-
- The 1,4-naphthoquinone scaffold in the design of cysteine protease inhibitors
-
A series of 1,4-naphthoquinone derivatives diversely substituted at C-2, C-3, C-5 and C-8, prepared by reaction of amines, amino acids and alcohols with commercial 1,4-naphthoquinones, has been evaluated against papain and bovine spleen cathepsin B. These
- Valente, Claudia,Moreira, Rui,Guedes, Rita C.,Iley, Jim,Jaffar, Mohammed,Douglas, Kenneth T.
-
p. 5340 - 5350
(2008/03/14)
-
- The Bsmoc group as a novel scaffold for the design of irreversible inhibitors of cysteine proteases
-
Carbamate and ester derivatives of the 1,1-dioxobenzo[b]thiophen-2-ylmethyloxycarbonyl (Bsmoc) scaffold react readily with thiols via a Michael addition at rates not significantly affected by the nature of the carboxylic or carbamic acid leaving group. These Michael acceptors are irreversible inhibitors of the cysteine proteases papain and human liver cathepsin B, displaying first-order kinetics with respect to inhibitor concentration. In contrast, none of the Bsmoc derivatives inhibited porcine pancreatic elastase, a serine protease.
- Iley, Jim,Moreira, Rui,Martins, Luisa,Guedes, Rita C.,Soares, Claudio M.
-
p. 2738 - 2741
(2007/10/03)
-
- Stereoselective synthesis of E-64 and related cysteine proteases inhibitors from 2,3-epoxyamides
-
The stereoselective synthesis of cathepsin inhibitors from indoline type epoxyamides is described. The use of this type of epoxyamides permitted the preparation of E-64 and CA-074 related compounds depending on the order in which the key steps, the oxidat
- Sarabia, Francisco,Sanchez-Ruiz, Antonio,Chammaa, Samy
-
p. 1691 - 1705
(2007/10/03)
-
- AZIRIDINE DERIVATIVES, THEIR PRODUCTION AND USE
-
The present invention relates to a compound of the formula: STR1 wherein R 1 and Q are independently an optionally esterified or amidated carboxyl group; R 2 is hydrogen, an acyl group or an optionally substituted hydrocarbon residue; X is a divalent hydrocarbon residue which may be substituted; or a salt thereof, which is useful as prophylactic and therapeutic agents of bone diseases and as agents for inhibiting thiol protease.
- -
-
-
- Mechanistic studies on the inactivation of papain by epoxysuccinyl inhibitors
-
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.
-
p. 3357 - 3366
(2007/10/03)
-
- Aziridine analogs of [[trans-(epoxysuccinyl)-L-leucyl]amino]-4- guanidinobutane (E-64) as inhibitors of cysteine proteases
-
Aziridine derivatives of E-64 have been synthesized, and their characterization against the cysteine proteases cathepsin B, cathepsin L, and papain is reported. The inhibition was found to be strongly pH-dependent, with maximum activity observed at pH 4, indicating that the protonated aziridinium ion form of the inhibitor is the more reactive form. At low pH, the peptide aziridine HO-(L)Az-Leu-NH-iAm inactivated papain with a second- order rate constant, k(inac)/K(j), of 7.0 x 104 M-1 s-1, a value very close to that observed with E-64 or with the corresponding epoxysuccinyl analog HO-(L)Eps-Leu-NH-iAm. This demonstrates that with the correct peptide sequence, aziridine analogs of E-64 can be good irreversible inhibitors of cysteine proteases. Substitution of the epoxysuccinyl moiety by an aziridine does not affect the specificity of inhibition against the three proteases used in this study. The D-diastereomer is the preferred (by 10-fold) diastereomer for the inhibition of cysteine proteases. The reactivity of both diastereomers of iBuNH-Az-LeuPro-OH against cathepsin B was also found to be much lower than that of iBuNH-(L)Eps-LeuPro-OH, which is a potent selective inhibitor of cathepsin B. These differences are attributed mainly to the presence of the protonated aziridine ring, which can modify the binding mode of aziridine analogs at the active site of cysteine proteases.
- Martichonok,Plouffe,Storer,Menard,Jones
-
p. 3078 - 3085
(2007/10/03)
-
- Synthesis of analogues of pepstatin. Effect of structure in subsites P(1'), P(2'), and P(2) on inhibition of porcine pepsin
-
A series of pepstatin analogues having structural variations in the P(2'), P(1'), and P(2) positions have been synthesized and tested for inhibition of porcine pepsin. The standard peptide for this study was Iva-Val-Sta-Ala-Iaa. Structural variations in t
- Rich,Salituro
-
p. 904 - 910
(2007/10/02)
-