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

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 Calabrese; Nicole L Caspers; Emily Cokorinos; Edward L Conn; Matthew S Dowling; David J Edmonds; Heather Eng; Dilinie P Fernando; Richard Frisbie; David Hepworth; James Landro; Yuxia Mao; Francis Rajamohan; Allan R Reyes; Colin R Rose; Tim Ryder; Andre Shavnya; Aaron C Smith; Meihua Tu; Angela C Wolford; Jun Xiao

doi:10.1021/acs.jmedchem.6b00866

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

J Med Chem. 2016 Sep 8;59(17):8068-81. doi: 10.1021/acs.jmedchem.6b00866. Epub 2016 Aug 20.

Authors

Kimberly O Cameron^{1

2}, Daniel W Kung^{1

2}, Amit S Kalgutkar^{1

2}, Ravi G Kurumbail^{1

2}, Russell Miller^{1

2}, Christopher T Salatto^{1

2}, Jessica Ward^{1

2}, Jane M Withka^{1

2}, Samit K Bhattacharya^{1

2}, Markus Boehm^{1

2}, Kris A Borzilleri^{1

2}, Janice A Brown^{1

2}, Matthew Calabrese^{1

2}, Nicole L Caspers^{1

2}, Emily Cokorinos^{1

2}, Edward L Conn^{1

2}, Matthew S Dowling^{1

2}, David J Edmonds^{1

2}, Heather Eng^{1

2}, Dilinie P Fernando^{1

2}, Richard Frisbie^{1

2}, David Hepworth^{1

2}, James Landro^{1

2}, Yuxia Mao^{1

2}, Francis Rajamohan^{1

2}, Allan R Reyes^{1

2}, Colin R Rose^{1

2}, Tim Ryder^{1

2}, Andre Shavnya^{1

2}, Aaron C Smith^{1

2}, Meihua Tu^{1

2}, Angela C Wolford^{1

2}, Jun Xiao^{1

2}

Affiliations

¹ Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
² Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, ⊥Cardiovascular, Metabolic and Endocrine Diseases Research Unit, #Worldwide Medicinal Chemistry, ∇Pharmacokinetics, Dynamics and Metabolism, ○Pharmaceutical Sciences, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.

PMID: 27490827
DOI: 10.1021/acs.jmedchem.6b00866

Abstract

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism*
Administration, Oral
Adsorption
Animals
Crystallography, X-Ray
Diabetic Nephropathies / drug therapy*
Dogs
Enzyme Activators / chemical synthesis
Enzyme Activators / chemistry*
Enzyme Activators / pharmacokinetics
Enzyme Activators / pharmacology
High-Throughput Screening Assays
Humans
Indazoles / chemical synthesis
Indazoles / chemistry
Indazoles / pharmacology
Indoles / chemical synthesis
Indoles / chemistry*
Indoles / pharmacokinetics
Indoles / pharmacology
Injections, Intravenous
Macaca fascicularis
Male
Models, Molecular
Protein Conformation
Rats

Substances

Enzyme Activators
Indazoles
Indoles
PF-6409577
AMP-Activated Protein Kinases