Decreasing the Rate of Metabolic Ketone Reduction in the Discovery of a Clinical Acetyl-CoA Carboxylase Inhibitor for the Treatment of Diabetes [electronic resource].
- Washington, D.C. : United States. Dept. of Energy. Office of Basic Energy Sciences, 2014. and Oak Ridge, Tenn. : Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy
- Physical Description:
- pages 10,512-10,526 : digital, PDF file
- Additional Creators:
- Argonne National Laboratory, United States. Department of Energy. Office of Basic Energy Sciences, National Institutes of Health (U.S.), and United States. Department of Energy. Office of Scientific and Technical Information
- Restrictions on Access:
- Free-to-read Unrestricted online access
- 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.
- Published through SciTech Connect., 11/25/2014., Journal of Medicinal Chemistry 57 24 ISSN 0022-2623 AM, David A. Griffith; Daniel W. Kung; William P. Esler; Paul A. Amor; Scott W. Bagley; Carine Beysen; Santos Carvajal-Gonzalez; Shawn D. Doran; Chris Limberakis; Alan M. Mathiowetz; Kirk McPherson; David A. Price; Eric Ravussin; Gabriele E. Sonnenberg; James A. Southers; Laurel J. Sweet; Scott M. Turner; Felix F. Vajdos., and Pfizer Inc.
- Funding Information:
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