1174013-25-2Relevant academic research and scientific papers
Discovery of an intravenous hepatoselective glucokinase activator for the treatment of inpatient hyperglycemia
Stevens, Benjamin D.,Litchfield, John,Pfefferkorn, Jeffrey A.,Atkinson, Karen,Perreault, Christian,Amor, Paul,Bahnck, Kevin,Berliner, Martin A.,Calloway, Jessica,Carlo, Anthony,Derksen, David R.,Filipski, Kevin J.,Gumkowski, Mike,Jassal, Charanjeet,MacDougall, Margit,Murphy, Brendan,Nkansah, Paul,Pettersen, John,Rotter, Charles,Zhang, Yan
, p. 6588 - 6592 (2014/01/06)
Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia. While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index. This work details the identification a hepatoselective GKA exhibiting the aforementioned properties.
Discovery of (S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl) propanamido)nicotinic acid as a hepatoselective glucokinase activator clinical candidate for treating type 2 diabetes mellitus
Pfefferkorn, Jeffrey A.,Guzman-Perez, Angel,Litchfield, John,Aiello, Robert,Treadway, Judith L.,Pettersen, John,Minich, Martha L.,Filipski, Kevin J.,Jones, Christopher S.,Tu, Meihua,Aspnes, Gary,Risley, Hud,Bian, Jianwei,Stevens, Benjamin D.,Bourassa, Patricia,D'Aquila, Theresa,Baker, Levenia,Barucci, Nicole,Robertson, Alan S.,Bourbonais, Francis,Derksen, David R.,MacDougall, Margit,Cabrera, Over,Chen, Jing,Lapworth, Amanda Lee,Landro, James A.,Zavadoski, William J.,Atkinson, Karen,Haddish-Berhane, Nahor,Tan, Beijing,Yao, Lili,Kosa, Rachel E.,Varma, Manthena V.,Feng, Bo,Duignan, David B.,El-Kattan, Ayman,Murdande, Sharad,Liu, Shenping,Ammirati, Mark,Knafels, John,Dasilva-Jardine, Paul,Sweet, Laurel,Liras, Spiros,Rolph, Timothy P.
, p. 1318 - 1333 (2012/04/18)
Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have bee
Multikilogram synthesis of a hepatoselective glucokinase activator
Dunetz, Joshua R.,Berliner, Martin A.,Xiang, Yanqiao,Houck, Timothy L.,Salingue, Fabrice H.,Chao, Wang,Yuandong, Chen,Shenghua, Wang,Huang, Yun,Farrand, Douglas,Boucher, Steven J.,Damon, David B.,Makowski, Teresa W.,Barrila, Mark T.,Chen, Raymond,Martinez, Isamir
, p. 1635 - 1645 (2013/02/25)
This work describes the process development and manufacture of early-stage clinical supplies of a hepatoselective glucokinase activator, a potential therapy for type 2 diabetes mellitus. Critical issues centered on challenges associated with the synthesis
FLUORINATED HETEROARYLS
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Page/Page column 30-31, (2010/04/03)
The present invention provides Formula (1A) XN O R 3 HN R 5 O R 4 R 2 R 1 (1A) 5 compounds that act as glucokinase activators; pharmaceutical compositions thereof; and methods of treating diseases, disorders, or conditions mediated by the glucokinase enzyme, where X, R 1, R 2, R 3, R 4, and R 5 are as described herein.
HETEROARYLS AMIDE DERIVATIVES AND THEIR USE AS GLUCOKINASE ACTIVATORS
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Page/Page column 33-34, (2010/04/06)
The present invention provides Formula (1A) compounds that act as glucokinase activators; pharmaceutical compositions thereof; and methods of treating diseases, disorders, or conditions mediated by glucokinase. X, Y, Z, R1, R2, R3, and R4 are as described herein.
Substituted Pyrazinone Amides
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Page/Page column 14-15, (2010/08/07)
The present invention provides compounds of Formula (I) that act as glucokinase activators; pharmaceutical compositions thereof; and methods of treating diseases, disorders, or conditions mediated by glucokinase. The variables R1, R2
Intrinsic electrophilicity of the 4-methylsulfonyl-2-pyridone scaffold in glucokinase activators: Role of glutathione-S-transferases and in vivo quantitation of a glutathione conjugate in rats
Litchfield, John,Sharma, Raman,Atkinson, Karen,Filipski, Kevin J.,Wright, Stephen W.,Pfefferkorn, Jeffrey A.,Tan, Beijing,Kosa, Rachel E.,Stevens, Benjamin,Tu, Meihua,Kalgutkar, Amit S.
scheme or table, p. 6262 - 6267 (2010/11/18)
Previous studies on the in vitro metabolism of 4-alkylsulfonyl-2-pyridone- based glucokinase activators revealed a facile, non-enzymatic displacement of the 4-alkylsulfonyl group by glutathione. In the present studies, a role for glutathione-S-transferases (GST) as catalysts in the desulfonylation reaction was demonstrated using a combination of human liver microsomes, human liver cytosol and human GSTs. The identification of a glutathione conjugate in circulation following intravenous administration of a candidate 4-methylsulfonyl-2-pyridone to rats confirmed the relevance of the in vitro findings.
Pyridones as glucokinase activators: Identification of a unique metabolic liability of the 4-sulfonyl-2-pyridone heterocycle
Pfefferkorn, Jeffrey A.,Lou, Jihong,Minich, Martha L.,Filipski, Kevin J.,He, Mingying,Zhou, Ru,Ahmed, Syed,Benbow, John,Perez, Angel-Guzman,Tu, Meihua,Litchfield, John,Sharma, Raman,Metzler, Karen,Bourbonais, Francis,Huang, Cong,Beebe, David A.,Oates, Peter J.
scheme or table, p. 3247 - 3252 (2010/03/03)
A promising area of novel anti-diabetic therapy involves identification of small molecule activators of the glucokinase enzyme to reduce blood glucose and normalize glucose stimulated insulin secretion. Herein, we report the identification and optimizatio
