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

Autor:	Jane M. Withka, Daniel W. Kung, Russell A. Miller, Matthew S. Dowling, Aaron C. Smith, Angela Wolford, Heather Eng, Janice A. Brown, Jun Xiao, Kris A. Borzilleri, Ravi G. Kurumbail, David J. Edmonds, Jessica Ward, Amit S. Kalgutkar, Colin R. Rose, Tim F. Ryder, Meihua Tu, Dilinie P. Fernando, Emily Cokorinos, David Hepworth, James A. Landro, Kimberly O. Cameron, Matthew F. Calabrese, Christopher T. Salatto, Francis Rajamohan, Andre Shavnya, Markus Boehm, Yuxia Mao, Allan R. Reyes, Richard K. Frisbie, Nicole Caspers, Edward L. Conn, Samit Kumar Bhattacharya
Rok vydání:	2016
Předmět:	Male Models Molecular 0301 basic medicine Adenosine monophosphate Indazoles Indoles Protein Conformation Administration Oral Enzyme Activators AMP-Activated Protein Kinases Crystallography X-Ray 03 medical and health sciences chemistry.chemical_compound Dogs 0302 clinical medicine AMP-activated protein kinase Drug Discovery medicine Animals Humans Diabetic Nephropathies Protein kinase A Indole test Indazole biology Activator (genetics) Chemistry AMPK Adenosine High-Throughput Screening Assays Rats Macaca fascicularis 030104 developmental biology Biochemistry 030220 oncology & carcinogenesis Injections Intravenous biology.protein Molecular Medicine Adsorption medicine.drug
Zdroj:	Journal of Medicinal Chemistry. 59:8068-8081
ISSN:	1520-4804 0022-2623
DOI:	10.1021/acs.jmedchem.6b00866
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::635e2459bb078e726c0e9a8f44099dcd https://doi.org/10.1021/acs.jmedchem.6b00866 Zobrazit plný text záznamu