Discovery and Preclinical Characterization of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577), a Direct Activator of Adenosine Monophosphate-activated Protein Kinase (AMPK), for the Potential Treatment of Diabetic Nephropathy
Adenosine monophosphate-activated protein kinase (AMPK) is a protein kinase involved in maintaining energy homeostasis within cells. On the basis of human genetic association data, AMPK activators were pursued for the treatment of diabetic nephropathy. Identification of an indazole amide high throughput screening (HTS) hit followed by truncation to its minimal pharmacophore provided an indazole acid lead compound. Optimization of the core and aryl appendage improved oral absorption and culminated in the identification of indole acid, PF-06409577 (7). Compound 7 was advanced to first-in-human trials for the treatment of diabetic nephropathy.
Cameron, Kimberly O.,Kung, Daniel W.,Kalgutkar, Amit S.,Kurumbail, Ravi G.,Miller, Russell,Salatto, Christopher T.,Ward, Jessica,Withka, Jane M.,Bhattacharya, Samit K.,Boehm, Markus,Borzilleri, Kris A.,Brown, Janice A.,Calabrese, Matthew,Caspers, Nicole L.,Cokorinos, Emily,Conn, Edward L.,Dowling, Matthew S.,Edmonds, David J.,Eng, Heather,Fernando, Dilinie P.,Frisbie, Richard,Hepworth, David,Landro, James,Mao, Yuxia,Rajamohan, Francis,Reyes, Allan R.,Rose, Colin R.,Ryder, Tim,Shavnya, Andre,Smith, Aaron C.,Tu, Meihua,Wolford, Angela C.,Xiao, Jun
p. 8068 - 8081
(2016/10/30)
INDOLE AND INDAZOLE COMPOUNDS THAT ACTIVATE AMPK
The present invention relates to indole and indazole compounds of Formula (I) that activate 5′ adenosine monophosphate-activated protein kinase (AMPK). The invention also encompasses pharmaceutical compositions containing these compounds and methods for treating or preventing diseases, conditions, or disorders ameliorated by activation of AMPK.
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Paragraph 0876
(2013/10/22)
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