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:
-
- Pfizer Worldwide Research and Development, Cambridge, MA (United States)
- KineMed Inc., Emeryville, CA (United States)
- 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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