- PEPTIDOMIMETICS FOR THE TREATMENT OF CORONAVIRUS AND PICORNAVIRUS INFECTIONS
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Compounds, compositions and methods for preventing, treating or curing a coronavirus, picornavirus, and/or Hepeviridae virus infection in human subjects or other animal hosts. Specific viruses that can be treated include enteroviruses. In one embodiment, the compounds can be used to treat an infection with a severe acute respiratory syndrome virus, such as human coronavirus 229E, SARS, MERS, SARS-CoV-1 (OC43), and SARS-CoV- 2. In another embodiment, the methods are used to treat a patient co-infected with two or more of these viruses, or a combination of one or more of these viruses and norovirus.
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Page/Page column 146
(2020/12/29)
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- Amidation of unactivated ester derivatives mediated by trifluoroethanol
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A catalytic amidation protocol mediated by 2,2,2-trifluoroethanol has been developed, facilitating the condensation of unactivated esters and amines, furnishing both secondary and tertiary amides. The complete scope and limitations of the method are described, along with modified conditions for challenging substrates such as acyclic secondary amines and chiral esters with retention of chiral integrity.
- McPherson, Christopher G.,Caldwell, Nicola,Jamieson, Craig,Simpson, Iain,Watson, Allan J. B.
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supporting information
p. 3507 - 3518
(2017/04/26)
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- Total synthesis method of hetiamacin A
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The invention relates to a total synthesis method of hetiamacin A. The method comprises the steps as follows: a compound (S)-3-((S)-1-amino-3-methylbutyl)-8-hydroxy 3,4-dibydro-isobenzopyran-1-ketone and a compound (2S,3S,4S)-2-amino-4-(carbobenzoxy amino
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Paragraph 0090; 0112; 0113
(2017/08/29)
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- Structure-guided design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Structure-activity relationships and biochemical, X-ray crystallographic, cell-based, and in vivo studies
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Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection.
- Galasiti Kankanamalage, Anushka C.,Kim, Yunjeong,Weerawarna, Pathum M.,Uy, Roxanne Adeline Z.,Damalanka, Vishnu C.,Mandadapu, Sivakoteswara Rao,Alliston, Kevin R.,Mehzabeen, Nurjahan,Battaile, Kevin P.,Lovell, Scott,Chang, Kyeong-Ok,Groutas, William C.
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p. 3144 - 3155
(2015/04/27)
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- Development of novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation
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Novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation were developed; some of them possess Ki values in the micromolar range. We studied the structure-activity relationship of these derivatives and we performed docking studies, which allowed us to find out the key interactions established by the inhibitors with the target enzyme. Biological results indicate that the nature of the P2 and P3 substituents and their binding to the S2/S3 pockets is strictly interdependent.
- Ettari, Roberta,Pinto, Andrea,Previti, Santo,Tamborini, Lucia,Angelo, Ilenia C.,La Pietra, Valeria,Marinelli, Luciana,Novellino, Ettore,Schirmeister, Tanja,Zappalà, Maria,Grasso, Silvana,De Micheli, Carlo,Conti, Paola
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p. 7053 - 7060
(2015/11/11)
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- Inhibition of norovirus 3CL protease by bisulfite adducts of transition state inhibitors
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Noroviruses are the most common cause of acute viral gastroenteritis, accounting for >21 million cases annually in the US alone. Norovirus infections constitute an important health problem for which there are no specific antiviral therapeutics or vaccines. In this study, a series of bisulfite adducts derived from representative transition state inhibitors (dipeptidyl aldehydes and α-ketoamides) was synthesized and shown to exhibit anti-norovirus activity in a cell-based replicon system. The ED 50 of the most effective inhibitor was 60 nM. This study demonstrates for the first time the utilization of bisulfite adducts of transition state inhibitors in the inhibition of norovirus 3C-like protease in vitro and in a cell-based replicon system. The approach described herein can be extended to the synthesis of the bisulfite adducts of other classes of transition state inhibitors of serine and cysteine proteases, such as α-ketoheterocycles and α-ketoesters.
- Mandadapu, Sivakoteswara Rao,Gunnam, Mallikarjuna Reddy,Tiew, Kok-Chuan,Uy, Roxanne Adeline Z.,Prior, Allan M.,Alliston, Kevin R.,Hua, Duy H.,Kim, Yunjeong,Chang, Kyeong-Ok,Groutas, William C.
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- Potent inhibition of norovirus by dipeptidyl α-hydroxyphosphonate transition state mimics
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The design, synthesis, and evaluation of a series of dipeptidyl α-hydroxyphosphonates is reported. The synthesized compounds displayed high anti-norovirus activity in a cell-based replicon system, as well as high enzyme selectivity.
- Mandadapu, Sivakoteswara Rao,Gunnam, Mallikarjuna Reddy,Galasiti Kankanamalage, Anushka C.,Uy, Roxanne Adeline Z.,Alliston, Kevin R.,Lushington, Gerald H.,Kim, Yunjeong,Chang, Kyeong-Ok,Groutas, William C.
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p. 5941 - 5944
(2013/10/22)
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- Self-assembled organogels formed by L-leucine dihydrazide derivative
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A new organogelator, benzyl (4-methyl-1-oxo-1-(2-hexadecanoylhydrazinyl) pentan-2-yl)carbamate (designated as Cbz-Leu-HdHz), was designed and synthesized, which could self-assemble in many organic solvents and form the thermally reversible physical supram
- Yu, Yang,Song, Ning,Jin, Shen,Shi, Wei,Zhai, Yuchun,Wang, Chuansheng
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p. 644 - 650
(2013/09/23)
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- MACROCYCLIC AND PEPTIDOMIMETIC COMPOUNDS AS BROAD-SPECTRUM ANTIVIRALS AGAINST 3C OR 3C-LIKE PROTEASES OF PICORNAVIRUSES, CALICIVIRUSES AND CORONAVIRUSES
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Antiviral protease inhibitors, including macrocylic transition state inhibitors and peptidomimetics are disclosed, along with related antiviral compounds, and methods of using the same to treat or prevent viral infection and disease. The compounds possess broad-spectrum activity against viruses that belong to the picornavirus-like supercluster, which include important human and animal pathogens including noroviruses, sapoviruses, enteroviruses, poliovirus, foot-and-mouth disease virus, hepatitis A virus, human rhinovirus (cause of common cold), human coronavirus (another cause of common cold), transmissible gastroenteritis virus, murine hepatitis virus, feline infectious peritonitis virus, and severe acute respiratory syndrome coronavirus.
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Page/Page column 39-40
(2013/11/19)
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- Carica papaya lipase catalysed resolution of β-amino esters for the highly enantioselective synthesis of (S)-dapoxetine
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An efficient synthesis of the (S)-3-amino-3-phenylpropanoic acid enantiomer has been achieved by Carica papaya lipase (CPL) catalysed enantioselective alcoholysis of the corresponding racemic N-protected 2,2,2-trifluoroethyl esters in an organic solvent. A high enantioselectivity (E > 200) was achieved by two strategies that involved engineering of the substrates and optimization of the reaction conditions. Based on the resolution of a series of amino acids, it was found that the structure of the substrate has a profound effect on the CPL-catalysed resolution. The enantioselectivity and reaction rate were significantly enhanced by switching the conventional methyl ester to an activated trifluoroethyl ester. When considering steric effects, the substituted phenyl and amino groups should not both be large for the CPL-catalysed resolution. The mechanism of the CPL-catalysed enantioselective alcoholoysis of the amino acids is discussed to delineate the substrate requirements for CPL-catalysed resolution. Finally, the reaction was scaled up, and the products were separated and obtained in good yields (≥ 80 %). The (S)-3-amino-3- phenylpropanoic acid obtained was used as a key chiral intermediate in the synthesis of (S)-dapoxetine with very high enantiomeric excess (> 99 %). A carica papaya lipase catalysed resolution of N-protected β-phenylalanine esters has been developed. High enantioselectivity was achieved by two strategies that involved engineering of the substrates and optimization of the reaction conditions. After 50 % conversion, the products were separated and used as key chiral intermediates for the synthesis of (S)-dapoxetine with > 99 % ee. Copyright
- You, Pengyong,Qiu, Jian,Su, Erzheng,Wei, Dongzhi
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p. 557 - 565
(2013/03/13)
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- Design, synthesis and biological evaluation of novel amino acid ureido derivatives as aminopeptidase N/CD13 inhibitors
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A series of amino acid ureido derivatives as aminopeptidase N (APN/CD13) inhibitors were synthesized and evaluated for their APN inhibitory activities and anti-cancer effects. The results showed that most of these amino acid ureido derivatives exhibited good inhibition against APN, several of which were better than Bestatin. The most active compound 12j (IC50 = 1.1 μM, compared with Bestatin IC50 = 8.1 μM) not only possessed much better APN inhibitory activity and anti-proliferation effect on cancer cells, but also exhibited significant block effect of human cancer cell invasion compared with the positive control, Bestatin. These amino acid ureido derivatives could be possibly developed as new APN inhibitors for cancer chemotherapy in the future.
- Su, Li,Jia, Yuping,Zhang, Lei,Xu, Yingying,Fang, Hao,Xu, Wenfang
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p. 3807 - 3815
(2012/08/27)
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- Synthesis and Antitubercular Activity of Novel Amino Acid Derivatives
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In this work, 17 new N-acylhydrazone derivatives of amino acids have been evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv. The compounds 8b, 8e, 8f, 9a-d, and 10c exhibited an important minimum inhibitory concentration activity between 12.5 and 50μg/mL, which can be compared with that of the tuberculostatic drug d-cycloserine (20μg/mL). In this work 17 new N-acylhydrazone derivatives of amino acids have been evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv. Eight compounds were non-cytotoxic and exhibited an important MIC activity between 12.5 and 50μg/mL, which can be compared with that of the tuberculostatic drug d-cycloserine (20μg/mL).
- Da Costa, Cristiane F.,Pinheiro, Alessandra C.,De Almeida, Mauro V.,Lourenco, Maria C.S.,De Souza, Marcus V.N.
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experimental part
p. 216 - 222
(2012/04/23)
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- Mild construction of 3-methyl tetramic acids enabling a formal synthesis of palau'imide
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A general method to construct 3-methyl-4-O-methylated tetramic acids displaying a C-5 stereocenter is presented. The synthetic sequence employs a SmI2-mediated cyclization, whereby the chirality of the emerging tetramic acid core is retained from the starting chiral amino acid. Application to palau'imide is discussed.
- Bai, Wen-Ju,Jackson, Stephen K.,Pettus, Thomas R. R.
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supporting information; experimental part
p. 3862 - 3865
(2012/09/22)
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- A favorable, narrow, δh Hansen-parameter domain for gelation of low-molecular-weight amino acid derivatives
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In recent years, the design of new low-molecular-weight gelators (LMWGs) has attracted considerable attention because of the interesting supramolecular architectures as well as industrial applications. In this context, the role of the organic solvent in d
- Curcio, Pasquale,Allix, Florent,Pickaert, Guillaume,Jamart-Gregoire, Brigitte
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scheme or table
p. 13603 - 13612
(2012/01/05)
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- Parallel synthesis of an oligomeric imidazole-4, 5-dicarboxamide library
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A library of oligomeric compounds was synthesized based on the imidazole-4, 5-dicarboxylic acid scaffold along with amino acid esters and chiral diamines derived from amino acids. The final compounds incorporate nonpolar amino acids (Leu, Phe, Trp), polar amino acids (Ser, Asp, Arg), and neutral amino acids (Gly, Ala), and were designed to be useful in screening for inhibitors of protein-protein interactions. Many of the protected and deprotected oligomers show evidence of conformational isomers persistent at room temperature in aqueous solution. A total of 317 final oligomers, out of 441 targeted compounds, were obtained in high analytical purity and of sufficient quantity to submit them for high-throughput screening as part of the NIH Roadmap.
- Xu, Zhigang,DiCesare, John C.,Baures, Paul W.
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supporting information; experimental part
p. 248 - 254
(2010/08/19)
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- Addition of allylzinc to a-amino acid-derived imines: Synthesis of diamino alcohols by Hydroboration
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Imines obtained by condensation of Z-pro- tected or Boc-protected α-amino aldehydes with α-amino tert-butyl esters or with O-silyl-protected amino alcohols were reacted with preformed allyl zinc yielding homoal- lylamines with yields around 50% and selectivities ranging from 50:50 to 90:10. Hydroboration of the terminal double bond furnished diamino alcohols with yields up to 97%. The configuration of the substrates was determined by X-ray-crystallographic analysis of a hydroboration product and comparison of physical data. Springer-Verlag 2010.
- Virlouvet, Mickael,Goesmann, Helmut,Feldmann, Claus,Podlech, Joachim
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scheme or table
p. 177 - 198
(2010/08/05)
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- Resolution of non-protein amino acids via Carica papaya lipase-catalyzed enantioselective transesterification
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Carica papaya lipase-catalyzed transesterification of the 2,2,2-trifluoroethyl esters of N-benzyloxycarbonylated dl-amino acids carrying aliphatic side chains proceeded smoothly and, in almost all the cases, enantiospecifically (E = >200), affording the l-methyl esters and leaving the d-trifluoroethyl esters intact.
- Miyazawa, Toshifumi,Onishi, Kazuki,Murashima, Takashi,Yamada, Takashi,Tsai, Shau-Wei
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p. 2569 - 2573
(2007/10/03)
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- Pyrolidine derivatives useful in treatment of hepatitis C virus infection
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The present invention relates to novel hepatitis C virus ("HCV") protease inhibitors or other flavivirus protease inhibitors of formula, pharmaceutical compositions containing one or more such inhibitors, methods for preparing such inhibitors, uses of the
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- BIOLOGICALLY ACTIVE COMPOUNDS
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Compounds of general formula (I) wherein: Z = CR3R4, where R3 and R4 are independently chosen from CO-7-alkyl P1 = CR5R6, P2 = O, CR7R8/sup
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Page 514-515
(2008/06/13)
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- A family of strong low-molecular-weight organogelators based on aminoacid derivatives
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A new family of potent aminoacid-type organogelators obtained via an easy and unexpensive way is described. We demonstrated that structural variations onto the side chains of the aminoacid derivatives allowed modulations of the gelation properties. The or
- Brosse, Nicolas,Barth, Danielle,Jamart-Grégoire, Brigitte
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p. 9521 - 9524
(2007/10/03)
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- Treatment of parasitic diseases by inhibition of cysteine proteases of the papain superfamily
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The present invention relates to compounds and pharmaceutical compositions which inhibit proteases, such as cysteine proteases. In particular, the present invention relates to compounds and pharmaceutical compositions which inhibit cysteine proteases of the papain superfamily. The compounds and pharmaceutical compositions of the present invention are useful for treating diseases, particularly parasitic diseases, which are mediated by such proteases. In particular, the present invention relates to a method of treating malaria by inhibiting the cysteine protease falcipain.
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- PROTEASE INHIBITORS
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Disclosed herein is a compound of the formula STR1 known as 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[4-(N,N-dimethylaminomethyl) benzyloxy]carbonyl-L-leucinyl]carbohydrazide; and pharmaceutically acceptable salts, hydrates and solvates thereof.
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- Structure-based design of cathepsin K inhibitors containing a benzyloxy- substituted benzoyl peptidomimetic
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Peptidomimetic cathepsin K inhibitors have been designed using binding models which were based on the X-ray crystal structure of an amino acid- based, active site-spanning inhibitor complexed with cathepsin K. These inhibitors, which contain a benzyloxybenzoyl group in place of a Cbz-leucine moiety, maintained good inhibitory potency relative to the amino acid-based inhibitor, and the binding models were found to be very predictive of relative inhibitor potency. The binding mode of one of the inhibitors was confirmed by X-ray crystallography, and the crystallographically determined structure is in close qualitative agreement with the initial binding model. These results strengthen the validity of a strategy involving iterative cycles of structure-based design, inhibitor synthesis and evaluation, and crystallographic structure determination for the discovery of peptidomimetic inhibitors.
- Thompson, Scott K.,Smith, Ward W.,Zhao, Baoguang,Halbert, Stacie M.,Tomaszek, Thaddeus A.,Tew, David G.,Levy, Mark A.,Janson, Cheryl A.,D'Alessio, Karla J.,McQueney, Michael S.,Kurdyla, Jeff,Jones, Christopher S.,Desjarlais, Renee L.,Abdel-Meguid, Sherin S.,Veber, Daniel F.
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p. 3923 - 3927
(2007/10/03)
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- A rapid reaction releasing the carboxyl terminal residues of peptides
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Alcoholysis of peptide oxazolones in alcohols containing dilute acid, such as 0.02M HCl, gives the C-terminal amino acid and the ester of the shortened peptide within 10 minutes at room temperature in 30-70% yields. This together with the finding that the peptide oxazolones can be formed within 3 minutes with alkylchloroformates enables the rapid removal of peptide C-terminal residues.
- Yagisawa, Shiroki,Urakami, Masako
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p. 7557 - 7560
(2007/10/03)
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- Novel peptidyl α-keto amide inhibitors of calpains and other cysteine proteases
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A series of new dipeptidyl α-keto amides of the general structure R1- L-Leu-D,L-AA-CONH-R2 were synthesized and evaluated as inhibitors for the cysteine proteases calpain I, calpain II, and cathepsin B. They combine 10 different N-protecting groups (R1), 3 amino acids residues in P1 (AA), and 44 distinct substituents on the α-keto amide nitrogen (R2). In general, calpain II was more sensitive to these inhibitors than calpain I, with a large number of inhibitors displaying dissociation constants (K(i)) in the 10-100 nM range. Calpain I was also effectively inhibited, but very low K(i) values were observed with a smaller number of inhibitors than with calpain II. Cathepsin B was weakly inhibited by most compounds in this study. The best inhibitors for calpain II were Z-Leu-Abu-CONH-CH2-CHOH-C6H5 (K(i) = 15 nM), Z-Leu-Abu-CONH-CH2-2-pyridyl (K(i) = 17 nM), and Z-Leu-Abu-CONH- CH2-C6H3(3,5(OMe)2) (K(i) = 22 nM). The best calpain I inhibitor in this study was Z-Leu-Nva-CONH-CH2-2-pyridyl (K(i) = 19 nM). The peptide α-keto amide Z-Leu-Abu-CONH-(CH2)2-3-indoly] was the best inhibitor for cathepsin B (K(i) = 31 nM). Some compounds acted as specific calpain inhibitors, with comparable activity on both calpains I and II and a lack of activity on cathepsin B (e.g., 40, 42, 48, 70). Others were specific inhibitors for calpain I (e.g., 73) or calpain II (e.g., 18, 19, 33, 35, 56). Such inhibitors may be useful in elucidating the physiological and pathological events involving these proteases and may become possible therapeutic agents.
- Li, Zhaozhao,Ortega-Vilain, Anne-Cécile,Patil, Girish S.,Chu, Der-Lun,Foreman,Eveleth, David D.,Powers, James C.
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p. 4089 - 4098
(2007/10/03)
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