Discovery and Preclinical Characterization of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1 H -indole-3-carboxylic Acid (PF-06409577), a Direct Activator of Adenosine Monophosphate-activated Protein Kinase (AMPK), for the Potential Treatment of Diabetic Nephropathy

作者：Kimberly O. Cameron, Daniel W. Kung, Amit S. Kalgutkar, Ravi G. Kurumbail, Russell Miller, Christopher T. Salatto, Jessica Ward, Jane M. Withka, Samit K. Bhattacharya, Markus Boehm, Kris A. Borzilleri, Janice A. Brown, Matthew F. Calabrese, Nicole Caspers, Emily Cokorinos, Edward L. Conn, Matthew Dowling, David J. Edmonds, Heather Eng, Dilinie P. Fernando, Richard K. Frisbie, David Hepworth, James A. Landro, Yuxia Mao, Francis Rajamohan, Allan R. Reyes, Colin R. Rose, Tim F. Ryder, Andre Shavnya, Aaron Smith, Meihua Tu, Angela Wolford, Jun Xiao · 发表于：Journal of Medicinal Chemistry · 年份：2016 · DOI：10.1021/acs.jmedchem.6b00866 · 被引用次数：119 · 研究领域：Metabolism, Diabetes, and Cancer、Pancreatic function and diabetes、Diabetes Treatment and Management

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.