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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

Journal Article · · Journal of Medicinal Chemistry
DOI:https://doi.org/10.1021/jm5016022· OSTI ID:1191716
 [1];  [2];  [1];  [1];  [2];  [3];  [1];  [2];  [2];  [1];  [2];  [1];  [4];  [1];  [2];  [2];  [3];  [2]
  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
+ Show Author Affiliations

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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); Pfizer Inc.; National Institutes of Health (NIH)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1191716
Journal Information:
Journal of Medicinal Chemistry, Vol. 57, Issue 24; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 56 works
Citation information provided by
Web of Science

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Cited By (14)

A combined drug discovery strategy based on machine learning and molecular docking journal March 2019
Human sebum requires de novo lipogenesis, which is increased in acne vulgaris and suppressed by acetyl-CoA carboxylase inhibition journal May 2019
Clinical assessment of hepatic de novo lipogenesis in non-alcoholic fatty liver disease journal September 2016
The utilization of spirocyclic scaffolds in novel drug discovery journal June 2016
Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats journal March 2016
Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models journal January 2019
Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: A randomized, double-blind, crossover study journal July 2017
The intriguing chemistry and biology of soraphens journal January 2019
Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data journal May 2017
Inhibiting both proline biosynthesis and lipogenesis synergistically suppresses tumor growth journal January 2020
3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) prevents high fat diet-induced insulin resistance via maintenance of hepatic lipid homeostasis journal September 2018
Dose-dependent quantitative effects of acute fructose administration on hepatic de novo lipogenesis in healthy humans journal July 2018
Metabolic Targets in Nonalcoholic Fatty Liver Disease journal January 2019
Modeling fructose-load-induced hepatic de-novo lipogenesis by model simplification journal January 2017

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