- Discovery of a Partial Glucokinase Activator Clinical Candidate: Diethyl ((3-(3-((5-(Azetidine-1-carbonyl)pyrazin-2-yl)oxy)-5-isopropoxybenzamido)-1H-pyrazol-1-yl)methyl)phosphonate (BMS-820132)
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Glucokinase (GK) is a key regulator of glucose homeostasis, and its small-molecule activators represent a promising opportunity for the treatment of type 2 diabetes. Several GK activators have been advanced into clinical trials and have demonstrated promising efficacy; however, hypoglycemia represents a key risk for this mechanism. In an effort to mitigate this hypoglycemia risk while maintaining the efficacy of the GK mechanism, we have investigated a series of amino heteroaryl phosphonate benzamides as ‘‘partial” GK activators. The structure-activity relationship studies starting from a “full GK activator” 11, which culminated in the discovery of the “partial GK activator” 31 (BMS-820132), are discussed. The synthesis and in vitro and in vivo preclinical pharmacology profiles of 31 and its pharmacokinetics (PK) are described. Based on its promising in vivo efficacy and preclinical ADME and safety profiles, 31 was advanced into human clinical trials.
- Barrish, Joel C.,Behnia, Kamelia,Bolton, Scott,Brigance, Robert P.,Cap, Michael,Chen, Bang-Chi,Chen, Sean,Chen, Xue-Qing,Cheng, Peter T. W.,Ellsworth, Bruce,Everlof, Gerry,Fuentes-Catanio, Helen G.,Fura, Aberra,Griffen, Steven,Gupta, Anuradha,Janovitz, Evan B.,Jones, Beverly,Kalinowski, Stephen,Kirby, Mark,Kopcho, Lisa,Krupinski, John,Krystek, Stanley R.,Kunselman, Lori,Langish, Robert A.,Leith, Leslie W.,Li, Yi-Xin,Liu, Heng,Ma, Xiaohui,Marcinkeviciene, Jovita,Mathur, Arvind,Meng, Wei,Muckelbauer, Jodi K.,Nielsen, Laura,O'Malley, Kevin,Pannacciulli, Nicola,Rampulla, Richard,Robl, Jeffrey A.,Ryono, Denis E.,Shi, Yan,Smirk, Rebecca,Spronk, Steven A.,Staal, Ada,Sulsky, Richard,Sun, Dawn,Sun, Jung-Hui,Swartz, Joann,Tao, Shiwei,Taylor, Joseph R.,Tino, Joseph A.,Wang, Aiying,Wang, Qi,Wang, Ying,Whaley, Jean,Williams, Kristin N.,Wong, Michael K. Y.,Wu, Dauh-Rurng,Xu, Carrie,Yang, Yanou,Zahler, Robert,Zalaznick, Jacob,Zebo, Rachel,Zhang, Hao,Zinker, Bradley A.
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p. 4291 - 4317
(2022/03/02)
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- Redesign of the Synthesis and Manufacture of an Azetidine-Bearing Pyrazine
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Commercial route definition for a glucokinase activator called for a re-evaluation of the synthesis and processes used to access multikilogram quantities of a pyrazine building block. The processes developed allowed a literature route to sodium 6-oxo-1H-pyrazine-3-carboxylate to be leveraged. One of these processes consisted of a highly selective decarboxylation that allowed the target building block to be accessed with complete regioselectivity in standard batch processing equipment. The presence of an azetidine ring in the target required the mitigation of impurity liabilities arising from the use of the hydrochloride salt of azetidine as an input material.
- Hose, David R. J.,Hopes, Phillip,Steven, Alan,Herber, Christian
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p. 241 - 246
(2018/02/23)
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- 2-(3,5-DISUBSTITUTEDPHENYL)PYRIMIDIN-4(3H)-ONE DERIVATIVES
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O N NH R3 R2 O R1 168 ABSTRACT The present invention provides a 2-(3,5-disubstitutedphenyl)pyrimidin- 4(3H)-one compound of Formula (I) 5 (I) or a pharmaceutically acceptable salt thereof wherein R 1, R2 and R3 are as defined herein. The compounds of Formula (I) have been found to act as glucokinase activators. Consequently, the compounds of Formula (I) and 10 the pharmaceutical compositions thereof are useful for the treatment of diseases, disorders, or conditions mediated by glucokinase.
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Page/Page column 37
(2012/01/06)
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- SUBSTITUTED INDAZOLE AMIDES AND THEIR USE AS GLUCOKINASE ACTIVATORS
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The present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein R1, R4, R6, X, Y and Z are as defined herein. The compounds of Formula (I) have been found to act as glucokinase activators. Consequently, the compounds of Formula (I) and the pharmaceutical compositions thereof are useful for the treatment of diseases, disorders, or conditions mediated by glucokinase.
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Page/Page column 40-41
(2010/10/03)
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- CHEMICAL PROCESS 632
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A process for preparing pharmaceutically active compounds of formula (I) or a salt thereof wherein R1, n, m, R3, R6, X1, X2, X3 and X4 are as defined in the specification, is described. Novel intermediates are also described and claimed.
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Page/Page column 18-19
(2010/08/22)
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- CRYSTALLINE POLYMORPHIC FORM 631
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A new polymorphic form of 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide, processes for making it and its use as an activator of glucokinase are described.
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- CHEMICAL COMPOUNDS
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The invention relates to a novel group of compounds of Formula (I) or a salt thereof: wherein R1, A and HET-1 are as described in the specification, which may be useful in the treatment or prevention of a disease or medical condition mediated through glucokinase (GLK) such as type 2 diabetes. The invention also relates to pharmaceutical compositions comprising said compounds, methods of treatment of diseases mediated by GLK using said compounds and methods for preparing compounds of Formula (I).
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Page/Page column 44-45
(2008/12/06)
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- NOVEL CRYSTALLINE COMPOUND
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A novel crystalline form of 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-1H-pyrazol-3-ylbenzamide is described in the specification. This compound is a glucokinase (GLK or GK) activator and useful as a pharmaceutical agent in the treatment or prevention of a disease or medical condition mediated through GLK, leading to a decreased glucose threshold for insulin secretion. Processes for the manufacture of the crystalline form, pharmaceutical compositions comprising the crystalline form and the use of the crystalline form in medical treatment are also described.
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Page/Page column 6
(2008/12/06)
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- 2-PHENYL SUBSTITUTED IMIDAZOL [4 , 5B] PYRIDINE/ PYRAZINE AND PURINE DERIVATIVES AS GLUCOKINASE MODULATORS
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Compounds of Formula (I), wherein R1- R10, A and X1 to X3 are as described in the specification, and their salts and pro-drugs, are activators of glucokinase (GLK) and are thereby useful in the treatment of, for example, type 2 diabetes. Processes for preparing compounds of formula (I) are also described.
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Page/Page column 108-109
(2010/11/25)
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