745053-49-0Relevant academic research and scientific papers
Scalable synthesis of a nonracemic α-arylpropionic acid via ketene desymmetrization for a glucokinase activator
Yamagami, Takafumi,Moriyama, Noriaki,Kyuhara, Masahiro,Moroda, Atsushi,Uemura, Takeshi,Matsumae, Hiroaki,Moritani, Yasunori,Inoue, Isao
, p. 437 - 445 (2014/04/17)
Process research and development for a synthesis of the chiral carboxylic acid (R)-2 as a key intermediate of the glucokinase activator (R)-1 is described. The construction of the stereocenter at the α-carbon is a key point for the synthesis of (R)-2. The proposed process utilizes desymmetrization of a ketene in situ generated from the corresponding racemic carboxylic acid Rac-2 with (R)-pantolactone as a chiral auxiliary followed by hydrolysis of the resulting ester. This key step has been successfully scaled up to 20 kg, which demonstrates that this synthetic approach is comparable with a previously reported approach via enantioselective hydrogenation.
Highly diastereoselective esterification of ketenes generated in situ from acyl chlorides with (R)-pantolactone derivatives
Yamagami, Takafumi,Hatsuda, Masanori,Utsugi, Masayuki,Kobayashi, Ryo,Moritani, Yasunori
, p. 7467 - 7470 (2013/12/04)
Our mechanistic investigations have revealed that Et3N is a key requirement for the highly diastereoselective formation of esters from the corresponding acyl chlorides with (R)-pantolactone via ketene-derived complexes. Furthermore, we have discovered that (R)-N-benzyl-pantolactam is a more effective chiral alcohol than (R)-pantolactone for the esterification of in situ generated ketenes. Ketene esterification with (R)-pantolactone derivatives is a powerful synthetic method for the synthesis of chiral α-arylpropionic acids. Our mechanistic investigations have revealed that Et3N is a key requirement for the predominant formation of ketenes from acyl chlorides, and (R)-N-benzylpantolactam was a much more effective chiral auxiliary.
Development of an enantioselective hydrogenation based synthesis of a glucokinase activator
Magnus, Nicholas A.,Braden, Timothy M.,Buser, Jonas Y.,Debaillie, Amy C.,Heath, Perry C.,Ley, Christopher P.,Remacle, Jacob R.,Varie, David L.,Wilson, Thomas M.
, p. 830 - 835 (2012/08/27)
This article describes the development and optimization of chemical reactions and subsequent multikilogram preparation of the glucokinase activator (R)-1 to fund clinical evaluation as a potential therapeutic for type II diabetes. The major process developments presented here are a Wittig olefination isomerization based synthesis of an E-acrylic acid, an optimized enantioselective hydrogenation of the E-acrylic acid, and a challenging final amide coupling.
An asymmetric synthesis of a chiral sulfone acid with concomitant hydrolysis and oxidation to enable the preparation of a glucokinase activator
DeBaillie, Amy C.,Magnus, Nicholas A.,Laurila, Michael E.,Wepsiec, James P.,Ruble, J. Craig,Petkus, Jeffrey J.,Vaid, Radhe K.,Niemeier, Jeffry K.,Mick, Joseph F.,Gunter, Thomas Z.
, p. 1538 - 1543 (2013/02/23)
This contribution describes the demonstration of an asymmetric synthesis of a glucokinase activator via protonation of the enolate generated from an alkylaryl ketene and (R)-pantolactone. Additionally, a one-pot hydrolysis/oxidation protocol with lithium hydroperoxide was developed to afford a chiral sulfone acid without degradation of the labile stereocenter.
Design, synthesis, and pharmacological evaluation of N-(4-mono and 4,5-disubstituted thiazol-2-yl)-2-aryl-3-(tetrahydro-2H-pyran-4-yl)propanamides as glucokinase activators
Li, Fuying,Zhu, Qingzhang,Zhang, Yi,Feng, Ying,Leng, Ying,Zhang, Ao
scheme or table, p. 3875 - 3884 (2010/08/05)
A series of N-thiazole substituted arylacetamides were designed on the basis of metabolic mechanism of the aminothiazole fragment as glucokinase (GK) activators for the treatment of type 2 diabetes. Instead of introducing a substituent to block the metabolic sensitive C-5 position on the thiazole core directly, a wide variety of C-4 or both C-4 and C-5 substitutions were explored. Compound R-9k bearing an iso-propyl group as the C-4 substituent was found possessing the highest GK activation potency with an EC50 of 0.026 μM. This compound significantly increased both glucose uptake and glycogen synthesis in rat primary cultured hepatocytes. Moreover, single oral administration of compound R-9k exerted significant reduction of blood glucose levels in both ICR and ob/ob mice. These promising results indicated that compound R-9k is a potent orally active GK activator, and is warranted for further investigation as a new anti-diabetic treatment.
Highly enantioselective hydrogenation of α-aryl-β-substituted acrylic acids catalyzed by Ir-SpinPHOX
Zhang, Yi,Han, Zhaobin,Li, Fuying,Ding, Kuiling,Zhang, Ao
supporting information; experimental part, p. 156 - 158 (2010/04/02)
The enantioselective hydrogenation of a series of challenging substrates, α-aryl-β-substituted acrylic acids, was realized with high efficiency and enantioselectivity (up to 96%) under the catalysis of Ir(i) complex of Spiro-based P,N ligand, SpinPHOX.
CRYSTALLINE (R)-2-(4-CYCLOPROPANESULPHONYL-PHENYL)-N-PYRAZIN-2-YL-3-(TETRAHYDROPYRAN-4-YL)-PROPIONAMIDE
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Page/Page column 4; 5, (2009/07/25)
Crystalline R-2-(4-cyclopropanesulfonyl-phenyl)-N-pyrazin-2-yl-3-(tetrahydropyran-4-yl)-propionamide and methods of its preparation and use are disclosed.
SAR, pharmacokinetics, safety, and efficacy of glucokinase activating 2-(4-sulfonylphenyl)-N-thiazol-2-ylacetamides: Discovery of PSN-GK1
Bertram, Lisa S.,Black, Daniel,Briner, Paul H.,Chatfield, Rosemary,Cooke, Andrew,Fyfe, Matthew C. T.,Murray, P. John,Naud, Frédéric,Nawano, Masao,Procter, Martin J.,Rakipovski, Günaj,Rasamison, Chrystelle M.,Reynet, Christine,Schofield, Karen L.,Shah, Vilas K.,Spindler, Felix,Taylor, Amanda,Turton, Roy,Williams, Geoffrey M.,Wong-Kai-In, Philippe,Yasuda, Kosuke
experimental part, p. 4340 - 4345 (2009/05/27)
Allosteric activators of the glucose-sensing enzyme glucokinase (GK) are currently attracting much interest as potential antidiabetic therapies because they can achieve powerful blood glucose lowering through actions in multiple organs. Here, the optimization of a weakly active high-throughput screening hit to (2R)-2-(4-cyclopropanesulfonylphenyl)-N-(5-fluorothiazol-2-yl)-3- (tetrahydropyran-4-yl)propionamide (PSN-GK1), a potent GK activator with an improved pharmacokinetic and safety profile, is described. Following oral administration, this compound elicited robust glucose lowering in rats.
NOVEL GLUCOKINASE ACTIVATORS AND METHODS OF USING SAME
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Page/Page column 34, (2008/06/13)
Compounds are provided which are glucokinase activators and thus are useful in treating diabetes and related diseases and have the structure wherein in the ring represents one or two double bonds; R1 is aryl or heteroaryl; R2 is halogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R5 is as defined herein; Z is O, S, S(O), S(O)2, or NR5a; X is S, O, N, NR3, or CR3; Y is NCR4 or N4; R3, R4, and R5 are as defined herein; R8 is aryl or heteroaryl; R6 and R7 are independently H, halogen, or alkyl; m is 0 or 1; and n is 0 to 3, or a pharmaceutically acceptable salt thereof. A method for treating diabetes and related diseases employing the above compounds is also provided.
NOVEL GLUCOKINASE ACTIVATORS AND METHODS OF USING SAME
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Page/Page column 65, (2008/06/13)
Compounds are provided which are phosphonate and phosphinate activators and thus are useful in treating diabetes and related diseases and have the structure wherein is a heteroaryl ring; R4 is —(CH2)n-Z-(CH2)m—PO(OR7)(OR8), —(CH2)nZ-(CH2)m—PO(OR7)Rg, —(CH2)n-Z-(CH2)m—OPO(OR7)Rg, —(CH2)nZ—(CH2)m—OPO(R9)(R10), or —(CH2)nZ—(CH2)m—PO(R9)(R10);R5 and R6 are independently selected from H, alkyl and halogen;Y is R7(CH2)s or is absent; andX, n, Z, m, R4, R5, R6, R7, and s are as defined herein; or a pharmaceutically acceptable salt thereof. A method for treating diabetes and related diseases employing the above compounds is also provided.
