- SUBSTITUTED AMINO TRIAZOLES USEFUL AS CHITINASE INHIBITORS
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Disclosed are amino triazole compounds of formula (I). These compounds are inhibitors of acidic mammalian chitinase and chitotriosidase. Also disclosed are methods of using the compounds to treat asthma reactions caused by allergens, as well as acute and chronic inflammatory diseases, autoimmune diseases, dental diseases, neurologic diseases, metabolic diseases, liver diseases, polycystic ovary syndrome, endometriosis, and cancer.
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Paragraph 0447
(2021/02/05)
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- Discovery of OATD-01, a First-in-Class Chitinase Inhibitor as Potential New Therapeutics for Idiopathic Pulmonary Fibrosis
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Chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) are the enzymatically active chitinases that have been implicated in the pathology of chronic lung diseases such as asthma and interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis. The clinical and preclinical data suggest that pharmacological inhibition of CHIT1 might represent a novel therapeutic approach in IPF. Structural modification of an advanced lead molecule 3 led to the identification of compound 9 (OATD-01), a highly active CHIT1 inhibitor with both an excellent PK profile in multiple species and selectivity against a panel of other off-targets. OATD-01 given orally once daily in a range of doses between 30 and 100 mg/kg showed significant antifibrotic efficacy in an animal model of bleomycin-induced pulmonary fibrosis. OATD-01 is the first-in-class CHIT1 inhibitor, currently completed phase 1b of clinical trials, to be a potential treatment for IPF.
- Koralewski, Robert,Dymek, Barbara,Mazur, Marzena,Sklepkiewicz, Piotr,Olejniczak, Sylwia,Czestkowski, Wojciech,Matyszewski, Krzysztof,Andryianau, Gleb,Niedziejko, Piotr,Kowalski, Michal,Gruza, Mariusz,Borek, Bart?omiej,Jedrzejczak, Karol,Bartoszewicz, Agnieszka,Pluta, El?bieta,Rymaszewska, Aleksandra,Kania, Magdalena,Rejczak, Tomasz,Piasecka, Sylwia,Mlacki, Michal,Mazurkiewicz, Marcin,Piotrowicz, Micha?,Salamon, Magdalena,Zagozdzon, Agnieszka,Napiorkowska-Gromadzka, Agnieszka,Bartlomiejczak, Aneta,Mozga, Witold,Dobrzański, Pawe?,Dzwonek, Karolina,Golab, Jakub,Nowotny, Marcin,Olczak, Jacek,Golebiowski, Adam
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supporting information
p. 15527 - 15540
(2020/11/17)
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- Design and synthesis of tripeptidyl furylketones as selective inhibitors against the β5 subunit of human 20S proteasome
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A series of tripeptidic proteasome inhibitors with furylketone as C-terminus were designed and synthesized. Biochemical evaluations against β1, β2 and β5 subunits revealed that they acted selectively on β5 subunit with IC50s against chymotrypsin-like (CT-L) activity in micromolar range. LC-MS/MS analysis of the ligand-20S proteasome mixture showed that the most potent compound 11m (IC50 = 0.18 μM) made no covalent modification on 20S proteasome. However, it was identified acting in a slowly reversible manner in wash-out assay and the reversibility was much lower than that of MG132, suggesting the possibility of these tripeptidic furylketones forming reversible covalent bonds with 20S proteasome. Several compounds were selected for anti-proliferative assay towards multiple cancer cell lines, and compound 11m displayed comparable potency to positive control (MG132) in all cell lines tested. Furthermore, the pharmacokinetic (PK) data in rats indicated 11m behaved similarly (Cmax, 2007 μg/L; AUC0?t, 680 μg/L·h; Vss, 0.66 L/kg) to the clinical used agent carfilzomib. All these data suggest 11m is a good lead compound to be developed to novel anti-tumor agent.
- Lü, Zirui,Li, Xiaona,Niu, Yan,Sun, Qi,Wang, Chao,Xi, Dandan,Xu, Fengrong,Xu, Ping,Zhou, Tongliang
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- SUBSTITUTED AMINO TRIAZOLES USEFUL AS HUMAN CHITINASE INHIBITORS
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Disclosed are amino triazole compounds substituted with a piperidinyl ring that is itself substituted with a heterocyclic ring. These compounds are inhibitors of acidic mammalian chitinase and chitotriosidase. Also disclosed are methods of using the compounds to treat asthma reactions caused by allergens, as well as acute and chronic inflammatory diseases, autoimmune diseases, dental diseases, neurologic diseases, metabolic diseases, liver diseases, polycystic ovary syndrome, endometriosis, and cancer.
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Page/Page column 138; 139
(2017/03/21)
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- New reagent for the introduction of Boc protecting group to amines: Boc-OASUD
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A new reagent, tert-butyl (2,4-dioxo-3-azaspiro [5,5] undecan-3-yl) carbonate (Boc-OASUD) for the preparation of N-Boc-amino acids is described. The Boc-OASUD reacts with amino acids and their esters at room temperature in the presence of a base and gives N-Boc-amino acids and their esters in good yields and purity. Introduction of the Boc group takes place without racemization. The Boc-OASUD, being a solid and more stable, is a better alternative to di-tert-butyl dicarbonate which is low melting and has to be dispensed in plastic containers than glass because of its poor stability.
- Maheswara Rao, B. Leela,Nowshuddin, Shaik,Jha, Anjali,Divi, Murali K.,Rao
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supporting information
p. 2127 - 2132
(2017/10/31)
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- METHOD FOR SYNTHESIZING OPTICALLY ACTIVE a-AMINO ACID USING CHIRAL METAL COMPLEX COMPRISING AXIALLY CHIRAL N-(2-ACYLARYL)-2-[5,7-DIHYDRO-6H-DIBENZO[c,e]AZEPIN-6-YL] ACETAMIDE COMPOUND AND AMINO ACID
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Objects of the present invention are to provide an industrially applicable method for producing an optically active α-amino acid in high yield and in a highly enantioselective manner, to provide a simple production method of an optically active α,α-disubstituted α-amino acid, and to provide an intermediate useful for the above production methods of an optically active α-amino acid and an optically active α,α-disubstituted α-amino acid. The present invention provides a production method of an optically active α-amino acid or a salt thereof, the production method comprising introducing a substituent into the α carbon in the α-amino acid moiety of a metal complex represented by the following Formula (1): by an alkylation reaction, an aldol reaction, the Michael reaction, or the Mannich reaction, and releasing an optically pure α-amino acid enantiomer or a salt thereof by acid decomposition of the metal complex.
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Paragraph 0300-0307
(2016/05/10)
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- Synthesis of an amidosulfonate-tagged biphenyl phosphine and its application in the Suzuki-Miyaura reaction affording biphenyl-substituted amino acids in water
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An amidosulfonate-tagged phosphinobiphenyl, viz triethylammonium 2-(dicyclohexylphosphino)-4′-{[(sulfonatomethyl)amino]carbonyl}biphenyl (3), was prepared in two steps from 2-(dicyclohexylphosphino)biphenyl-4′-carboxylic acid and fully characterized including the crystal structure determination. As a highly polar phosphine ligand, compound 3 was employed in the Pd-catalyzed Suzuki-Miyaura cross-coupling of N-Boc protected 4-bromo and 4-chlorophenylalanine with aromatic boronic acids to afford the corresponding biphenyls in aqueous N,N-dimethylformamide or pure water. The coupling was demonstrated to proceed very well and without the loss of the Boc protecting group when the bromo-substituted substrate is reacted in the presence of 1 mol.% of Pd/3 catalyst in water at 40 °C. Reactions with boronic acids bearing electron-withdrawing substituents and, mainly, those with the less reactive chlorophenylalanine substrate required slightly higher reaction temperature and more catalyst to achieve similar results.
- Schulz, Ji?í,Císa?ová, Ivana,?těpni?ka, Petr
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- METHOD FOR SYNTHESIZING OPTICALLY ACTIVE α-AMINO ACID USING CHIRAL METAL COMPLEX COMPRISING AXIALLY CHIRAL N-(2-ACYLARYL)-2-[5,7-DIHYDRO-6H-DIBENZO[c,e]AZEPIN-6-YL]ACETAMIDE COMPOUND AND AMINO ACID
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Objects of the present invention are to provide an industrially applicable method for producing an optically active ±-amino acid in high yield and in a highly enantioselective manner, to provide a simple production method of an optically active ±,±-disubstituted ±-amino acid, and to provide an intermediate useful for the above production methods of an optically active ±-amino acid and an optically active ±,±-disubstituted ±-amino acid. The present invention provides a production method of an optically active ±-amino acid or a salt thereof, the production method comprising introducing a substituent into the ± carbon in the ±-amino acid moiety of a metal complex represented by the following Formula (1): by an alkylation reaction, an aldol reaction, the Michael reaction, or the Mannich reaction, and releasing an optically pure ±-amino acid enantiomer or a salt thereof by acid decomposition of the metal complex.
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Paragraph 0484; 0486; 0488; 0499
(2016/11/17)
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- Discovery of pyrrolopyrimidine inhibitors of Akt
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The discovery and optimization of a series of pyrrolopyrimidine based protein kinase B (Pkb/Akt) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent inhibition of all three Akt isoforms and knockdown of phospho-PRAS40 levels in LNCaP cells and tumor xenografts.
- Blake, James F.,Kallan, Nicholas C.,Xiao, Dengming,Xu, Rui,Bencsik, Josef R.,Skelton, Nicholas J.,Spencer, Keith L.,Mitchell, Ian S.,Woessner, Richard D.,Gloor, Susan L.,Risom, Tyler,Gross, Stefan D.,Martinson, Matthew,Morales, Tony H.,Vigers, Guy P.A.,Brandhuber, Barbara J.
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scheme or table
p. 5607 - 5612
(2010/11/17)
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- Collection of traceable compounds and uses thereof
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The use of a collection of compounds of general formula (I), wherein: n is 0 or 1; p represents an integer between 1 and 6; r represents an integer between 1 and 12; R1 and R′1 represent in particular a hydrogen atom; R2 represents an amino acid side chain or an amino acid derivative; R3 represents a group derived from a carboxylic acid, bearing a basic entity; R4 represents in particular an alkyl group containing 1 to 10 carbon atoms; and A represents a hydrogen atom, a protecting group or a tracing group, in particular a fluorophor, a coloring agent or a quencher, for determining, through binding studies, ligands of receptors whose ligand is unknown or whose ligand useful for carrying out specific affinity binding assays is unknown.
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- Process for production of optically active n-protected-n-methyl-phenylalanine derivative
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There is provided a process for industrially and efficiently producing an optically active N-protected-N-methyl-4-halogenophenylalanine at a high purity, which is useful as an intermediate for the production of pharmaceutical agents. An optically active N-protected-N-methyl-4-halogenophenylalanine (including the free form and/or the salt form thereof) purified to a high purity is produced by way of the deposition and isolation in the form of salt (DCHA salt or the like) from an optically active N-protected-N-methyl-4-halogenophenylalanine containing at least the optical isomer thereof as an impurity. Because the intended compound at a high purity can be recovered and obtained at a high yield, the process of the present invention is very useful as a process for producing the intermediate for the production of pharmaceutical agents.
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- NOVEL THIAZINE OR PYRAZINE DERIVATIVES
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An object of the present invention is to synthesize novel compounds having 3-oxo-3, 4-dihydro-2H-1, 4-thiazine or 2-oxo-1, 2, 3, 4-tetrahydropyrazine as a main skeleton. The present invention relates to compounds represented by the following general formula [I] and salts thereof. In the formula, X is S or R6-(A2)n-N, R1 and R2 are H, alkyl, cycloalkyl or aryl, R3 and R4 are H, alkyl, cycloalkyl, aryl or aromatic heterocycles, R5 is H, alkyl, cycloalkyl, aryl or -A3-A4-R7, R6 is H, alkyl, cycloalkyl, OH, alkoxy, aryl, aryloxy or an aromatic heterocycle, R7 is H, alkyl, OH, alkoxy, aryl, aryloxy, amino, alkylamino, arylamino, an aromatic heterocycle or a nonaromatic heterocycle, A1 is alkylene, A2 is carbonyl or sulfonyl, A3 is alkylene, and A4 is carbonyl or oxalyl.
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- 1-ARYL-2-ACYLAMINO-ETHANE COMPOUNDS AND THEIR USE AS NEUROKININ ESPECIALLY NEUROKININ 1 ANTAGONISTS
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1-Aryl-2-acylaminoethane compounds of formula I STR1 wherein R. sub.1-R 4, X and Am are as defined in the description, have valuable pharmaceutical properties and are especially effective as NK-1 antagonists.
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- Aryl hydrazides as linkers for solid phase synthesis which are cleavable under mild oxidative conditions
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We have developed an acid/base stable aryl hydrazide linker which is readily coupled to solid phase resins. Cleavage is specific and facile, requiring a copper (II) catalyst, base and a nucleophile to proceed. The conditions are compatible with all 20 proteinogenic amino acids and quantitative cleavage is achieved within 2 hours at 20°C to give peptides with C-terminal acid, amide or ester functionalities. Aryl hydrazides also offer scope as simple 'traceless' linkers.
- Millington, Christopher R.,Quarrell, Rachel,Lowe, Gordon
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p. 7201 - 7204
(2007/10/03)
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- Protecting Groups that can be Removed through Photochemical Electron Transfer: Mechanistic and Product Studies on Photosensitized Release of Carboxylates from Phenacyl Esters
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Photolysis of electron-donating photosensitizers in the presence of various phenacyl esters (PhCOCH2-OCOR) results in C-O bond scission leading to the formation of acetophenone (PhCOCH3) and the corresponding carboxylic acid (RCO2H). Preparative experiments showed that the carboxylic acids are generated in high or quantitative isolated yields. It is argued that this reaction is initiated by a photoinduced electron transfer from the excited state sensitizer to the phenacyl ester. The latter process forms the anion radical of the phenacyl ester which in turn undergoes rapid C-O bond scission leading to the phenacyl radical and the corresponding carboxylate anion. This mechanism is supported by the following observations. (1) The phenacyl esters quench fluorescence from the sensitizers. (2) Analysis of the redox potentials of the sensitizer excited states and the substrates shows that the proposed electron transfer step is exergonic by 15-20 kcal/mol. (3) The byproducts are indicative of the proposed ion radical intermediates. In particular N-methylaniline is detected when N4Y-dimethylaniline is used as a sensitizer. (4) Competing processes are observed in phenacyl esters whose acid components are themselves labile to single-electron transfer. For example, phenacyl 4-bromophenylacetate showed bromide elimination in competition with deprotection.
- Banerjee, Anamitro,Falvey, Daniel E.
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p. 6245 - 6251
(2007/10/03)
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- A Formal Total Synthesis of the ACE Inhibitor K-13. An Application of Arene-Ruthenium Chemistry to Complex Chemical Synthesis
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Stoichiometric ruthenium activation of 4-chlorophenylalanine derivatives toward nucleophilic substitution, using phenoxide nucleophiles that are derived from protected dipeptides, allowed the formation of isodityrosine derivatives that are synthetic precursors to the ACE inhibitor K-13.An evaluation of carboxyl blocking groups revealed that a 2-bromoethyl ester is the most useful in terms of its compatibility with ruthenium complexation and subsequent nucleophile addition but that its removal is problematic.Conversion to iodoethyl ester using Finkelstein reaction conditions, in the presence of the peptide and amino acid functionality, provided a solution to this problem, since the iodoethyl group was easily removed on treatment with samarium diiodide.
- Pearson, Anthony J.,Lee, Kieseung
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p. 2304 - 2313
(2007/10/02)
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- DIISOPROPYLETHYLAMINE ELIMINATES DIPEPTIDE FORMATION DURING THE ACYLATION OF AMINO ACIDS USING BENZOYL CHLORIDE AND SOME ALKYL CHLOROFORMATES
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Acylation of amino acids using benzoyl chloride in aqueous alkali leads to benzoylamino acids containing one percent of benzoyldipeptide.Use of diisopropylethylamine instead of sodium hydroxide as base eliminates the side reaction responsible for the contaminant.Ethoxycarbonylamino acids are advantageously prepared in the same manner using ethyl chloroformate or diethyl dicarbonate.The latter gives rise to some N-substituted dipeptide when used in aqueous alkali.The method is unsatisfactory for the benzyloxycarbonylation of amino acids.Use of 9-fluorenylmethyl chloroformate and diisopropylethylamine gives the pure derivative of leucine in moderate yield.
- Chen, Francis M. F.,Benoiton, N. Leo
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p. 1224 - 1227
(2007/10/02)
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