- A chemoselective oxidation of monosubstituted ethylene glycol: Facile synthesis of optically active α-hydroxy acids
-
A mild and efficient method for the synthesis of optically active α-hydroxy acids through chemoselective oxidation of monosubstituted ethylene glycols using the TEMPO-NaOCl reagent system is described. It is evident from our studies that the solvent, pH and reaction temperature are very crucial for the success of this oxidation. The versatility of this method has been demonstrated with a variety of aliphatic, aromatic and carbohydrate substrates bearing various functional groups. the Partner Organisations 2014.
- Chinthapally, Kiran,Baskaran, Sundarababu
-
p. 4305 - 4309
(2014/06/23)
-
- Discovery of an intravenous hepatoselective glucokinase activator for the treatment of inpatient hyperglycemia
-
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.
- 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)
-
- Multikilogram synthesis of a hepatoselective glucokinase activator
-
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
- 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)
-
- 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
-
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
- 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.
-
experimental part
p. 1318 - 1333
(2012/04/18)
-
- HETEROARYLS AMIDE DERIVATIVES AND THEIR USE AS GLUCOKINASE ACTIVATORS
-
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.
- -
-
Page/Page column 33
(2010/04/06)
-
- 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
-
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.
- 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)
-
- FLUORINATED HETEROARYLS
-
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.
- -
-
Page/Page column 30
(2010/04/03)
-
- Substituted Pyrazinone Amides
-
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
- -
-
Page/Page column 14
(2010/08/07)
-
- Pyridones as glucokinase activators: Identification of a unique metabolic liability of the 4-sulfonyl-2-pyridone heterocycle
-
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
- 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)
-