- Peripheral Selective Oxadiazolylphenyl Alanine Derivatives as Tryptophan Hydroxylase 1 Inhibitors for Obesity and Fatty Liver Disease
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Tryptophan hydroxylase 1 (TPH1) has been recently suggested as a promising therapeutic target for treating obesity and fatty liver disease. A new series of 1,2,4-oxadiazolylphenyl alanine derivatives were identified as TPH1 inhibitors. Among them, compound 23a was the most active in vitro, with an IC50 (half-maximal inhibitory concentration) value of 42 nM, showed good liver microsomal stability, and showed no significant inhibition of CYP and hERG. Compound 23a inhibited TPH1 in the peripheral tissue with limited BBB penetration. In high-fat diet-fed mice, 23a reduced body weight gain, body fat, and hepatic lipid accumulation. Also, 23a improved glucose intolerance and energy expenditure. Taken together, compound 23a shows promise as a therapeutic agent for the treatment of obesity and fatty liver diseases.
- Bae, Eun Jung,Choi, Won Gun,Pagire, Haushabhau S.,Pagire, Suvarna H.,Parameswaran, Saravanan,Choi, Jun-Ho,Yoon, Jihyeon,Choi, Won-Il,Lee, Ji Hun,Song, Jin Sook,Bae, Myung Ae,Kim, Mijin,Jeon, Jae-Han,Lee, In-Kyu,Kim, Hail,Ahn, Jin Hee
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p. 1037 - 1053
(2021/02/05)
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- Novel derivatives of urea and use thereof
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The present invention relates to a novel urea derivative compound and 5HT thereof. 2A The present invention relates to the use of antagonists as antagonists for the prevention or treatment of neuropsychiatric disorders, degenerative brain diseases, propagated disorders and/or metabolic diseases.
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- NOVEL TRYPTOPHAN HYDROXYLASE INHIBITOR AND PHARMACEUTICAL COMPOSITION INCLUDING SAME
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The present invention relates to a novel tryptophan hydroxylase inhibitor and a pharmaceutical composition including same, wherein the novel tryptophan hydroxylase inhibitor has an excellent inhibitory effect on TPH1, and thus can be usefully used for the prevention or treatment of disorders, such as metabolic disorders, cancer, digestive or cardiovascular system disorders, related to TPH1 activity. In particular, the novel tryptophan hydroxylase inhibitor has an excellent treatment effect on inflammatory bowel disorders, and thus can be usefully used for the treatment of inflammatory bowel disorder.
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Paragraph 0074; 0186
(2020/07/15)
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- Design, Synthesis, and Biological Evaluation of New Peripheral 5HT2A Antagonists for Nonalcoholic Fatty Liver Disease
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Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent worldwide, causing serious liver complications, including nonalcoholic steatohepatitis. Recent findings suggest that peripheral serotonin (5-hydroxytryptamine, 5HT) regulates energy homeostasis, including hepatic lipid metabolism. More specifically, liver-specific 5HT2A knockout mice exhibit alleviated hepatic lipid accumulation and hepatic steatosis. Here, structural modifications of pimavanserin (CNS drug), a 5HT2A antagonist approved for Parkinson's disease, led us to synthesize new peripherally acting 5HT2A antagonists. Among the synthesized compounds, compound 14a showed good in vitro activity, good liver microsomal stability, 5HT subtype selectivity, and no significant inhibition of CYP and hERG. The in vitro and in vivo blood-brain barrier permeability study proved that 14a acts peripherally. Compound 14a decreased the liver weight and hepatic lipid accumulation in high-fat-diet-induced obesity mice. Our study suggests new therapeutic possibilities for peripheral 5HT2A antagonists in NAFLD.
- Kim, Minhee,Hwang, Inseon,Pagire, Haushabhau S.,Pagire, Suvarna H.,Choi, Wonsuk,Choi, Won Gun,Yoon, Jihyeon,Lee, Won Mi,Song, Jin Sook,Yoo, Eun Kyung,Lee, Seung Mi,Kim, Mi-Jin,Bae, Myung Ae,Kim, Dooseop,Lee, Heejong,Lee, Eun-Young,Jeon, Jae-Han,Lee, In-Kyu,Kim, Hail,Ahn, Jin Hee
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p. 4171 - 4182
(2020/04/30)
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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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- Nonsolvent application of ionic liquids: Organo-catalysis by 1-alkyl-3-methylimidazolium cation based room-temperature ionic liquids for chemoselective N-tert-butyloxycarbonylation of amines and the influence of the C-2 hydrogen on catalytic efficiency
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1-Alkyl-3-methylimidazolium cation based ionic liquids efficiently catalyze N-tert-butyloxycarbonylation of amines with excellent chemoselectivity. The catalytic role of the ionic liquid is envisaged as "electrophilic activation" of di-tert-butyl dicarbonate (Boc2O) through bifurcated hydrogen bond formation with the C-2 hydrogen of the 1-alkyl-3-methylimidazolium cation and has been supported by a downfield shift of the imidazolium C-2 hydrogen of 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([bmim][NTf2]) from δ 8.39 to 8.66 in the presence of Boc2O in the 1H NMR and a drastic reduction of the catalytic efficiency with 1-butyl-2,3-dimethylimidazolium ionic liquids that are devoid of the C-2 hydrogen. The differential time required for reaction with aromatic and aliphatic amines has offered means for selective N-t-Boc formation during inter and intramolecular competitions. Preferential N-t-Boc formation with secondary aliphatic amine has been achieved in the presence of primary aliphatic amine. Comparison of the catalytic efficiency for N-t-Boc formation with a common substrate revealed that [bmim][NTf2] is superior to the reported Lewis acid catalysts.
- Sarkar, Anirban,Roy, Sudipta Raha,Parikh, Naisargee,Chakraborti, Asit K.
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experimental part
p. 7132 - 7140
(2011/10/08)
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- Useful reagents for introduction of Boc and Fmoc protective groups to amines: Boc-DMT and Fmoc-DMT
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New amino-protecting reagents, Boc-DMT and Fmoc-DMT, were prepared, and found to be useful for the introduction of Boc and Fmoc groups into amines. Both the reagents can protect various amines including amino acids in good yield in aqueous media. Since the reagents are neither unstable nor irritating, they are practically useful. Georg Thieme Verlag Stuttgart.
- Hioki, Kazuhito,Kinugasa, Mizuho,Kishimoto, Michiko,Fujiwara, Miho,Tani, Shohei,Kunishima, Munetaka
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p. 1931 - 1933
(2007/10/03)
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- HClO4-SiO2 as a new, highly efficient, inexpensive and reusable catalyst for N-tert-butoxycarbonylation of amines
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Perchloric acid adsorbed on silica-gel (HClO4-SiO2) was found to be a new, highly efficient, inexpensive and reusable catalyst for chemoselective N-tert-butoxycarbonylation of amines at room temperature and under solvent-free conditions. The Royal Society of Chemistry 2006.
- Chakraborti, Asit K.,Chankeshwara, Sunay V.
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p. 2769 - 2771
(2008/03/28)
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- Indium(III) halides as new and highly efficient catalysts for N-tert-butoxycarbonylation of amines
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Indium(III) bromide and chloride efficiently catalysed the N-tert-butoxycarbonylation of amines with (Boc)2O at room temperature and under solvent-free conditions. Various aromatic, heteroaromatic and aliphatic amines were converted to N-tert-butylcarbamates in excellent yields in short times. Chiral amines, esters of α-amino acids and β-amino alcohols afforded optically pure N-t-Boc derivatives in high yields. The reactions were chemoselective and no competitive side reactions such as isocyanate, urea, and N,N-di-t-Boc formation were observed. Chemoselective conversion to N-tert-butylcarbamates took place with amino alcohols without any formation of oxazolidinones. Georg Thieme Verlag Stuttgart.
- Chankeshwara, Sunay V.,Chakraborti, Asit K.
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p. 2784 - 2788
(2008/02/05)
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- NOVEL BIAROMATIC COMPOUNDS WHICH ACTIVATE PPARγ TYPE RECEPTORS, AND USE THEREOF IN COSMETIC OR PHARMACEUTICAL COMPOSITIONS
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The invention relates to novel biaromatic compounds which correspond to the general formula (I), and also to a process for preparing them and to their use in pharmaceutical compositions intended for use in human or veterinary medicine (in dermatology, and also in the field of cardiovascular diseases, immune diseases and/or diseases associated with lipid metabolism), or alternatively in cosmetic compositions.
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- Inhibitors of alpha4mediated cell adhesion
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The present invention relates to a phenylalanine derivative of Formula (I) wherein X1 is a halogen atom, X2 is a halogen atom, Q is a CH2R— is a carboxyl group which may be esterified; or a pharmaceutically acceptable salt thereof.
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- O'-(epoxyalkyl)tyrosines and (epoxyalkyl)phenylalanine as irreversible inactivators of serine proteases: Synthesis and inhibition mechanism
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A series of O'-(epoxyalkyl)tyrosines and a carboxy terminal (epoxyalkyl)tyrosine and -phenylalanine were synthesized as potential serine protease inhibitors. N-Acetyl derivatives showed irreversible inactivation vis-a-vis subtilisin, while the N-benzoyl ones were specific toward chymotrypsin. The most potent inactivation of chymotrypsin was achieved by a O'-(3,4-epoxybutyl)-L-tyrosine derivative. The inactivation was shown to be stereospecific since a D derivative led to no irreversible inactivation. Placement of the epoxyalkyl group at the carboxy terminus led to potent rapid inactivation. Under these conditions some of the activity was later recovered. The two classes of inactivators (O'-epoxyalkyl and carboxy-epoxyalkyl) appear to operate by different mechanisms. Most importantly, it was found that irreversible inactivation by O'-(epoxyalkyl)-L-tyrosine only resulted if the carboxy terminus was a substrate (i.e. a compound with free carboxy terminus did not lead to inactivation). The ultimate activity kinetic assay (Daniels, S.B.; et al. J. Biol. Chem. 1983, 258, 15046-15053.) indicated that the epoxyalkyl group on the phenolic oxygen had an optimal length of four carbons with respect to the turnover ratio (the ratio of molecules undergoing turnover compared to those that inactivate the enzyme) for chymotrypsin. A different kinetic assay (Ashani, Y.; Wins P.; Wilson, I.B. Biochim. Biophys. Acta 1972, 284, 427-434.) demonstrated that substratelike turnover was proceeding at considerably slower rates than for the corresponding true substrates and with rate-limiting deacylation of the acyl-enzyme. Amino acid analysis subsequent to acid hydrolysis demonstrated that Met had been selectively alkylated by the O'-(epoxyalkyl)tyrosine derivative. By contrast, α-chymotrypsin inactivated with N-benzoyl-L-Phe-2,3-epoxypropyl ester then subjected to amino acid analysis showed no change in the content of any amino acid that would serve as a potential nucleophile to the inhibitor. Yet, the L-Phe content increased, indicating that a covalent bond had been formed between the inhibitor and the enzyme. Either the bond between the inhibitor and the enzyme did not withstand the hydrolytic conditions and/or there was less than 10% decrease in the amino acids with nucleophilic side chains upon inactivation. Finally, two tripeptides containing O'-(epoxyalkyl)-L-tyrosines were synthesized [N-(tert-butoxycarbonyl)-L-alanyl-L-alanyl-O'-(2,3-epoxypropyl)-L-tyro sine ethyl ester and N-(trifluoroacteyl)-L-valyl-O'(2,3-epoxypropyl)-L-tyrosyl-L-valine methyl ester] as potential elastase inhibitors and were found to reversibly and competitively inhibit porcine pancreatic elastase.
- Tous,Bush,Tous,Jordan
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p. 1620 - 1634
(2007/10/02)
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- SYNTHESIS OF AMINO ACID ESTERS BY PAPAIN
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A wide range of N-Boc-amino acid esters were synthesized from N-Boc-amino acids and alcohol using papain as catalyst.Suitable biphasic reaction mixtures were found for most amino acids to achieve high yield of ester synthesis.With N-Boc-L-aspartic and glutamic acids only the α carbonyl group esterified, without racemisation.
- Cantacuzene, D.,Pascal, F.,Guerreiro, C.
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p. 1823 - 1826
(2007/10/02)
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- Phase transfer catalysis in the tert-butyloxycarbonylation of alcohols, phenols, enols, and thiols with di-tert-butyl dicarbonate
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It is shown that the tert-butyloxycarbonylation of phenols, alcohols, enols, and thiols can be accomplished by reaction of these functionalities with di-tert-butyl bicarbonate under phase transfer conditions.The reactions proceed in high yield and can also be used for the introduction of t-BOC groups onto functionalized polymer backbones such as poly(p-hydroxystyrene).In addition, a study is made of the selectivity towards tert-butyloxycarbonilation of various polyfunctional compounds.
- Houlihan, F.,Bouchard, J.,Frechet, J. M. J.,Willson, C. G.
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p. 153 - 162
(2007/10/02)
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