Acyl Glucuronide Metabolites of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577) and Related Indole-3-carboxylic Acid Derivatives are Direct Activators of Adenosine Monophosphate-Activated Protein Kinase (AMPK)

Ryder, Tim F.; Calabrese, Matthew F.; Walker, Gregory S.; Cameron, Kimberly O.; Reyes, Allan R.; Borzilleri, Kris A.; Delmore, Jake; Miller, Russell; Kurumbail, Ravi G.; Ward, Jessica; Kung, Daniel W.; Brown, Janice A.; Edmonds, David J.; Eng, Heather; Wolford, Angela C.; Kalgutkar, Amit S.

doi:10.1021/acs.jmedchem.8b00807

Acyl Glucuronide Metabolites of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577) and Related Indole-3-carboxylic Acid Derivatives are Direct Activators of Adenosine Monophosphate-Activated Protein Kinase (AMPK)

Journal Article · Mon Jul 23 00:00:00 EDT 2018 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.8b00807· OSTI ID:1544833

Ryder, Tim F. ^[1]; Calabrese, Matthew F. ^[1]; Walker, Gregory S. ^[1]; Cameron, Kimberly O. ^[2]; Reyes, Allan R. ^[2]; Borzilleri, Kris A. ^[1]; Delmore, Jake ^[2]; Miller, Russell ^[2]; Kurumbail, Ravi G. ^[1]; Ward, Jessica ^[2]; ^[1]; Brown, Janice A. ^[1]; ^[2]; Eng, Heather ^[1]; Wolford, Angela C. ^[1]; ^[2]

Pfizer Worldwide Research & Development, Groton, CT (United States)
Pfizer Worldwide Research & Development, Cambridge, MA (United States)

Studies on indole-3-carboxylic acid derivatives as direct activators of human adenosine monophosphate-activated protein kinase (AMPK) α1β1γ1 isoform have culminated in the identification of PF-06409577 (1), PF-06885249 (2), and PF-06679142 (3) as potential clinical candidates. Compounds 1–3 are primarily cleared in animals and humans via glucuronidation. In this paper, we describe the biosynthetic preparation, purification, and structural characterization of the glucuronide conjugates of 1–3. Spectral characterization of the purified glucuronides M1, M2, and M3 indicated that they were acyl glucuronide derivatives. In vitro pharmacological evaluation revealed that all three acyl glucuronides retained selective activation of β1-containing AMPK isoforms. Inhibition of de novo lipogenesis with representative parent carboxylic acids and their respective acyl glucuronide conjugates in human hepatocytes demonstrated their propensity to activate cellular AMPK. Cocrystallization of the AMPK α1β1γ1 isoform with 1–3 and M1–M3 provided molecular insights into the structural basis for AMPK activation by the glucuronide conjugates.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Industrial Macromolecular Crystallography Association; USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1544833

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 16 Vol. 61; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Acyl Glucuronide Metabolites of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577) and Related Indole-3-carboxylic Acid Derivatives are Direct Activators of Adenosine Monophosphate-Activated Protein Kinase (AMPK)

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