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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

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. 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. In conclusion, this demonstration of target engagement validates the use of compound 9 to evaluate the role of DNL in human disease.

Authors:
 [1];  [2];  [1];  [1];  [2];  [3];  [1];  [2];  [2];  [1];  [2];  [1];  [4];  [1];  [2];  [2];  [3];  [2]
+ Show Author Affiliations
  1. Pfizer Worldwide Research and Development, Cambridge, MA (United States)
  2. Pfizer Worldwide Research and Development, Groton, CT (United States)
  3. KineMed, Inc., Emeryville, CA (United States)
  4. Louisiana State Univ., Baton Rouge, LA (United States). Pennington Biomedical Research Center
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); Pfizer Inc.; National Institutes of Health (NIH)
OSTI Identifier:
1191716
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
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; 60 APPLIED LIFE 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.
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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
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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. Tue . "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. https://www.osti.gov/servlets/purl/1191716.
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@article{osti_1191716,
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 = {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. 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. In conclusion, this demonstration of target engagement validates the use of compound 9 to evaluate the role of DNL in human disease.},
doi = {10.1021/jm5016022},
journal = {Journal of Medicinal Chemistry},
number = 24,
volume = 57,
place = {United States},
year = {Tue Nov 25 00:00:00 EST 2014},
month = {Tue Nov 25 00:00:00 EST 2014}
}
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https://doi.org/10.1021/jm5016022
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Stimulation of Fat Oxidation, but no Sustained Reduction of Hepatic Lipids by Prolonged Pharmacological Inhibition of Acetyl CoA Carboxylase
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