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Title: 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

Journal Article · · Journal of Medicinal Chemistry
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  1. Pfizer Worldwide Research & Development, Cambridge, MA (United States)
  2. Pfizer Worldwide Research & Development, Groton, CT (United States)
  3. Pfizer Worldwide Research &, Development, Groton, CT (United States)
  4. Pfizer Worldwide Research &, Development, Groton, CT (United States)
+ Show Author Affiliations

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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
INDUSTRY; USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1368232
Journal Information:
Journal of Medicinal Chemistry, Vol. 59, Issue 17; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 88 works
Citation information provided by
Web of Science

References (32)

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Cited By (18)

Purinergic Signalling: Therapeutic Developments journal September 2017
Synthesis and structure–activity relationships of pyrazolo‐[3,4‐ b ]pyridine derivatives as adenosine 5'‐monophosphate‐activated protein kinase activators journal July 2019
The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs journal September 2017
Prediction of Optimal Drug Schedules for Controlling Autophagy journal February 2019
Miniaturized and Automated Synthesis of Biomolecules—Overview and Perspectives journal April 2019
Targeting AMPK in Diabetes and Diabetic Complications: Energy Homeostasis, Autophagy and Mitochondrial Health journal October 2019
Neural-Symbolic Machine Learning for Retrosynthesis and Reaction Prediction journal February 2017
Targeting of lipid metabolism with a metabolic inhibitor cocktail eradicates peritoneal metastases in ovarian cancer cells journal July 2019
A Novel Phenylchromane Derivative Increases the Rate of Glucose Uptake in L6 Myotubes and Augments Insulin Secretion from Pancreatic Beta-Cells by Activating AMPK journal October 2017
Identification of a novel 2-oxindole fluorinated derivative as in vivo antitumor agent for prostate cancer acting via AMPK activation journal March 2018
All-Trans-Retinoic Acid Suppresses Neointimal Hyperplasia and Inhibits Vascular Smooth Muscle Cell Proliferation and Migration via Activation of AMPK Signaling Pathway journal May 2019
6-Chloro-5-[4-(1-Hydroxycyclobutyl)Phenyl]-1 H -Indole-3-Carboxylic Acid is a Highly Selective Substrate for Glucuronidation by UGT1A1, Relative to β -Estradiol journal September 2018
Immunologic and endocrine functions of adipose tissue: implications for kidney disease journal December 2017
Selective Activation of AMPK β 1-Containing Isoforms Improves Kidney Function in a Rat Model of Diabetic Nephropathy journal March 2017
Direct Activation of Adenosine Monophosphate-Activated Protein Kinase (AMPK) by PF-06409577 Inhibits Flavivirus Infection through Modification of Host Cell Lipid Metabolism journal July 2018
Prediction of Optimal Drug Schedules for Controlling Autophagy preprint January 2018
2-[2-(4-(trifluoromethyl)phenylamino)thiazol-4-yl]acetic acid (Activator-3) is a potent activator of AMPK journal June 2018
Identification of Direct Activator of Adenosine Monophosphate-Activated Protein Kinase (AMPK) by Structure-Based Virtual Screening and Molecular Docking Approach journal June 2017

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
indoles
assays
rodent models
peptides and proteins
cell and molecular biology