- Discovery of MK-8722: A Systemic, Direct Pan-Activator of AMP-Activated Protein Kinase
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5′-Adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of mammalian energy homeostasis and has been implicated in mediating many of the beneficial effects of exercise and weight loss including lipid and glucose trafficking. As such,
- Feng, Danqing,Biftu, Tesfaye,Romero, F. Anthony,Kekec, Ahmet,Dropinski, James,Kassick, Andrew,Xu, Shiyao,Kurtz, Marc M.,Gollapudi, Anantha,Shao, Qing,Yang, Xiaodong,Lu, Ku,Zhou, Gaochao,Kemp, Daniel,Myers, Robert W.,Guan, Hong-Ping,Trujillo, Maria E.,Li, Cai,Weber, Ann,Sebhat, Iyassu K.
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supporting information
p. 39 - 44
(2018/05/04)
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- Hit-to-Lead Optimization and Discovery of 5-((5-([1,1′-Biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic Acid (MK-3903): A Novel Class of Benzimidazole-Based Activators of AMP-Activated Protein Kinase
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AMP-activated protein kinase (AMPK) plays an essential role as a cellular energy sensor and master regulator of metabolism in eukaryotes. Dysregulated lipid and carbohydrate metabolism resulting from insulin resistance leads to hyperglycemia, the hallmark of type 2 diabetes mellitus (T2DM). While pharmacological activation of AMPK is anticipated to improve these parameters, the discovery of selective, direct activators has proven challenging. We now describe a hit-to-lead effort resulting in the discovery of a potent and selective class of benzimidazole-based direct AMPK activators, exemplified by 5-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid, 42 (MK-3903). Compound 42 exhibited robust target engagement in mouse liver following oral dosing, leading to improved lipid metabolism and insulin sensitization in mice.
- Lan, Ping,Romero, F. Anthony,Wodka, Dariusz,Kassick, Andrew J.,Dang, Qun,Gibson, Tony,Cashion, Daniel,Zhou, Gaochao,Chen, Yuli,Zhang, Xiaoping,Zhang, Aihua,Li, Ying,Trujillo, Maria E.,Shao, Qing,Wu, Margaret,Xu, Shiyao,He, Huaibing,Mackenna, Deidre,Staunton, Jocelyn,Chapman, Kevin T.,Weber, Ann,Sebhat, Iyassu K.,Makara, Gergely M.
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p. 9040 - 9052
(2017/11/14)
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- PARASITICIDAL COMPOSITIONS COMPRISING BENZIMIDAZOLE DERIVATIVES, METHODS AND USES THEREOF
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The invention relates to oral, topical or injectable compositions for combating liver fluke parasites in mammals, comprising at least one benzimidazole derivative active agent. The invention also provides for an improved method for eradicating and controlling liver fluke parasite infections and infestations in a mammal comprising administering the compositions of the invention to the mammal in need thereof.
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Paragraph 0148
(2013/11/05)
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- NOVEL CYCLIC BENZIMIDAZOLE DERIVATIVES USEFUL ANTI-DIABETIC AGENTS
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Novel compounds of the structural formula (I) are activators of AMP-protein kinase and are useful in the treatment, prevention and suppression of diseases mediated by the AMPK- activated protein kinase. The compounds of the present invention are useful in
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Page/Page column 66
(2011/09/30)
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- NOVEL CYCLIC BENZIMIDAZOLE DERIVATIVES USEFUL ANTI-DIABETIC AGENTS
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Novel compounds of the structural formula (I) are activators of AMP-protein kinase and are useful in the treatment, prevention and suppression of diseases mediated by the AMPK- activated protein kinase. The compounds of the present invention are useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.
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Page/Page column 81
(2010/05/14)
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- NOVEL CYCLIC BENZIMIDAZOLE DERIVATIVES USEFUL AS ANTI-DIABETIC AGENTS
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Novel compounds of the structural formula (I) are activators of AMP-protein kinase and are useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention are useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.
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Page/Page column 36
(2010/04/25)
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- NOVEL CYCLIC BENZIMIDAZOLE DERIVATIVES USEFUL ANTI-DIABETIC AGENTS
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Novel compounds of the structural formula (I) are activators of AMP-protein kinase and are useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention are useful in the treatment of Type 2 diabetes, hyperglycemia, Metabolic Syndrome, obesity, hypercholesterolemia, and hypertension
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Page/Page column 75
(2010/05/13)
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- NOVEL CYCLIC BENZIMIDAZOLE DERIVATIVES USEFUL ANTI-DIABETIC AGENTS
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Novel compounds of the structural formula (I) are activators of AMP-protein kinase and are useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention are useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.
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Page/Page column 81
(2010/05/14)
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