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Title: Decreasing the Rate of Metabolic Ketone Reduction in the Discovery of a Clinical Acetyl-CoA Carboxylase Inhibitor for the Treatment of Diabetes

Abstract

We found that Acetyl-CoA carboxylase (ACC) inhibitors offer significant potential for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis, and cancer. However, the identification of tool compounds suitable to test the hypothesis in human trials has been challenging. An advanced series of spirocyclic ketone-containing ACC inhibitors recently reported by Pfizer were metabolized in vivo by ketone reduction, which complicated human pharmacology projections. Here, we disclose that this metabolic reduction can be greatly attenuated through introduction of steric hindrance adjacent to the ketone carbonyl. Incorporation of weakly basic functionality improved solubility and led to the identification of 9 as a clinical candidate for the treatment of T2DM. Phase I clinical studies demonstrated dose-proportional increases in exposure, single-dose inhibition of de novo lipogenesis (DNL), and changes in indirect calorimetry consistent with increased whole-body fatty acid oxidation. This demonstration of target engagement validates the use of compound 9 to evaluate the role of DNL in human disease.

Authors:
 [1];  [1];  [1];  [1];  [1];  [2];  [1];  [1];  [1];  [1];  [1];  [1];  [3];  [1];  [1];  [1];  [2];  [1]
  1. Pfizer Worldwide Research and Development, Cambridge, MA (United States)
  2. KineMed Inc., Emeryville, CA (United States)
  3. Louisiana State Univ., Baton Rouge, LA (United States)
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1229006
Report Number(s):
BNL-111081-2015-JA
Journal ID: ISSN 0022-2623
DOE Contract Number:  
SC00112704
Resource Type:
Journal Article
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 57; Journal Issue: 24; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Griffith, David A., Kung, Daniel W., Esler, William P., Amor, Paul A., Bagley, Scott W., Beysen, Carine, Carvajal-Gonzalez, Santos, Doran, Shawn D., Limberakis, Chris, Mathiowetz, Alan M., McPherson, Kirk, Price, David A., Ravussin, Eric, Sonnenberg, Gabriele E., Southers, James A., Sweet, Laurel J., Turner, Scott M., and Vajdos, Felix F. Decreasing the Rate of Metabolic Ketone Reduction in the Discovery of a Clinical Acetyl-CoA Carboxylase Inhibitor for the Treatment of Diabetes. United States: N. p., 2014. Web. doi:10.1021/jm5016022.
Griffith, David A., Kung, Daniel W., Esler, William P., Amor, Paul A., Bagley, Scott W., Beysen, Carine, Carvajal-Gonzalez, Santos, Doran, Shawn D., Limberakis, Chris, Mathiowetz, Alan M., McPherson, Kirk, Price, David A., Ravussin, Eric, Sonnenberg, Gabriele E., Southers, James A., Sweet, Laurel J., Turner, Scott M., & Vajdos, Felix F. Decreasing the Rate of Metabolic Ketone Reduction in the Discovery of a Clinical Acetyl-CoA Carboxylase Inhibitor for the Treatment of Diabetes. United States. https://doi.org/10.1021/jm5016022
Griffith, David A., Kung, Daniel W., Esler, William P., Amor, Paul A., Bagley, Scott W., Beysen, Carine, Carvajal-Gonzalez, Santos, Doran, Shawn D., Limberakis, Chris, Mathiowetz, Alan M., McPherson, Kirk, Price, David A., Ravussin, Eric, Sonnenberg, Gabriele E., Southers, James A., Sweet, Laurel J., Turner, Scott M., and Vajdos, Felix F. 2014. "Decreasing the Rate of Metabolic Ketone Reduction in the Discovery of a Clinical Acetyl-CoA Carboxylase Inhibitor for the Treatment of Diabetes". United States. https://doi.org/10.1021/jm5016022.
@article{osti_1229006,
title = {Decreasing the Rate of Metabolic Ketone Reduction in the Discovery of a Clinical Acetyl-CoA Carboxylase Inhibitor for the Treatment of Diabetes},
author = {Griffith, David A. and Kung, Daniel W. and Esler, William P. and Amor, Paul A. and Bagley, Scott W. and Beysen, Carine and Carvajal-Gonzalez, Santos and Doran, Shawn D. and Limberakis, Chris and Mathiowetz, Alan M. and McPherson, Kirk and Price, David A. and Ravussin, Eric and Sonnenberg, Gabriele E. and Southers, James A. and Sweet, Laurel J. and Turner, Scott M. and Vajdos, Felix F.},
abstractNote = {We found that Acetyl-CoA carboxylase (ACC) inhibitors offer significant potential for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis, and cancer. However, the identification of tool compounds suitable to test the hypothesis in human trials has been challenging. An advanced series of spirocyclic ketone-containing ACC inhibitors recently reported by Pfizer were metabolized in vivo by ketone reduction, which complicated human pharmacology projections. Here, we disclose that this metabolic reduction can be greatly attenuated through introduction of steric hindrance adjacent to the ketone carbonyl. Incorporation of weakly basic functionality improved solubility and led to the identification of 9 as a clinical candidate for the treatment of T2DM. Phase I clinical studies demonstrated dose-proportional increases in exposure, single-dose inhibition of de novo lipogenesis (DNL), and changes in indirect calorimetry consistent with increased whole-body fatty acid oxidation. This demonstration of target engagement validates the use of compound 9 to evaluate the role of DNL in human disease.},
doi = {10.1021/jm5016022},
url = {https://www.osti.gov/biblio/1229006}, journal = {Journal of Medicinal Chemistry},
issn = {0022-2623},
number = 24,
volume = 57,
place = {United States},
year = {Fri Dec 26 00:00:00 EST 2014},
month = {Fri Dec 26 00:00:00 EST 2014}
}

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Design, synthesis, and structure–activity relationships of novel spiro-piperidines as acetyl-CoA carboxylase inhibitors
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ElogD o ct :  A Tool for Lipophilicity Determination in Drug Discovery. 2. Basic and Neutral Compounds
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Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase
journal, January 2012


Synthesis of 7-Oxo-dihydrospiro[indazole-5,4′-piperidine] Acetyl-CoA Carboxylase Inhibitors
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De novo lipogenesis in humans: metabolic and regulatory aspects
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Soraphen, an inhibitor of the acetyl-CoA carboxylase system, improves peripheral insulin sensitivity in mice fed a high-fat diet
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Liver fat and lipid oxidation in humans
journal, October 2009


Malonyl-CoA, a Key Signaling Molecule in Mammalian Cells
journal, August 2008


Disordered Lipid Metabolism and the Pathogenesis of Insulin Resistance
journal, April 2007


Works referencing / citing this record:

A combined drug discovery strategy based on machine learning and molecular docking
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Human sebum requires de novo lipogenesis, which is increased in acne vulgaris and suppressed by acetyl-CoA carboxylase inhibition
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Clinical assessment of hepatic de novo lipogenesis in non-alcoholic fatty liver disease
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The utilization of spirocyclic scaffolds in novel drug discovery
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Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats
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Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models
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Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data
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Inhibiting both proline biosynthesis and lipogenesis synergistically suppresses tumor growth
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3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) prevents high fat diet-induced insulin resistance via maintenance of hepatic lipid homeostasis
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Metabolic Targets in Nonalcoholic Fatty Liver Disease
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Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data
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