Skip to main content
OSTI.GOVU.S. Department of Energy Office of Scientific and Technical Information
U.S. Department of Energy
Office of Scientific and Technical Information
 

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:1229006
 [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)
+ Show Author Affiliations

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.

Research Organization:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI ID:
1229006
Report Number(s):
BNL--111081-2015-JA
Journal Information:
Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 24 Vol. 57; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English

References (34)

Liver fat and lipid oxidation in humans journal October 2009
ElogD o ct :  A Tool for Lipophilicity Determination in Drug Discovery. 2. Basic and Neutral Compounds journal July 2001
N -{3-[2-(4-Alkoxyphenoxy)thiazol-5-yl]-1-methylprop-2-ynyl}carboxy Derivatives as Acetyl-CoA Carboxylase InhibitorsImprovement of Cardiovascular and Neurological Liabilities via Structural Modifications journal March 2007
Refinement of Macromolecular Structures by the Maximum-Likelihood Method journal May 1997
Acetyl-coenzyme A carboxylases: Versatile targets for drug discovery journal January 2006
Stimulation of Fat Oxidation, but no Sustained Reduction of Hepatic Lipids by Prolonged Pharmacological Inhibition of Acetyl CoA Carboxylase journal August 2011
Data processing and analysis with the autoPROC toolbox journal March 2011
Synthesis of 7-Oxo-dihydrospiro[indazole-5,4′-piperidine] Acetyl-CoA Carboxylase Inhibitors journal January 2012
Scaling and assessment of data quality journal December 2005
Design, synthesis, and structure–activity relationships of novel spiro-piperidines as acetyl-CoA carboxylase inhibitors journal June 2012
Symmetrical approach of spiro-pyrazolidinediones as acetyl-CoA carboxylase inhibitors journal July 2012
Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase journal January 2012
Soraphen, an inhibitor of the acetyl-CoA carboxylase system, improves peripheral insulin sensitivity in mice fed a high-fat diet journal October 2009
Malonyl-CoA, a Key Signaling Molecule in Mammalian Cells journal August 2008
On the treatment of negative intensity observations journal July 1978
Synthesis and Structure−Activity Relationships of N -{3-[2-(4-Alkoxyphenoxy)thiazol-5-yl]-1- methylprop-2-ynyl}carboxy Derivatives as Selective Acetyl-CoA Carboxylase 2 Inhibitors journal June 2006
Inhibition of acetyl-CoA carboxylase 2 enhances skeletal muscle fatty acid oxidation and improves whole-body glucose homeostasis in db/db mice journal April 2012
Structure-guided Inhibitor Design for Human Acetyl-coenzyme A Carboxylase by Interspecies Active Site Conversion journal December 2011
Disordered Lipid Metabolism and the Pathogenesis of Insulin Resistance journal April 2007
Overview of the CCP 4 suite and current developments journal March 2011
Overview of the CCP 4 suite and current developments journal March 2011
Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2 journal April 2010
Crystal Structure of the Carboxyltransferase Domain of Acetyl-Coenzyme A Carboxylase in Complex with CP-640186 journal September 2004
Refinement of Macromolecular Structures by the Maximum-Likelihood Method journal May 1997
Lipid-induced insulin resistance: unravelling the mechanism journal June 2010
Data processing and analysis with the autoPROC toolbox journal March 2011
Identification and Synthesis of Novel Inhibitors of Acetyl-CoA Carboxylase with in Vitro and in Vivo Efficacy on Fat Oxidation journal December 2010
De novo lipogenesis in humans: metabolic and regulatory aspects journal April 1999
Piperazine Oxadiazole Inhibitors of Acetyl-CoA Carboxylase journal December 2013
XDS journal January 2010
Structure-guided Inhibitor Design for Human Acetyl-coenzyme A Carboxylase by Interspecies Active Site Conversion journal December 2011
Complementary α-alkylation approaches for a sterically hindered spiro[pyrazolopyranpiperidine]ketone journal May 2012
Lipid-induced insulin resistance: unravelling the mechanism journal June 2010
Isozyme-nonselective N-Substituted Bipiperidylcarboxamide Acetyl-CoA Carboxylase Inhibitors Reduce Tissue Malonyl-CoA Concentrations, Inhibit Fatty Acid Synthesis, and Increase Fatty Acid Oxidation in Cultured Cells and in Experimental Animals journal September 2003

Cited By (14)

Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models journal January 2019
Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data journal May 2017
The utilization of spirocyclic scaffolds in novel drug discovery journal June 2016
Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: A randomized, double-blind, crossover study journal July 2017
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
Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats journal March 2016
Inhibiting both proline biosynthesis and lipogenesis synergistically suppresses tumor growth journal January 2020
A combined drug discovery strategy based on machine learning and molecular docking journal March 2019
The intriguing chemistry and biology of soraphens journal January 2019
Clinical assessment of hepatic de novo lipogenesis in non-alcoholic fatty liver disease journal September 2016
Human sebum requires de novo lipogenesis, which is increased in acne vulgaris and suppressed by acetyl-CoA carboxylase inhibition journal May 2019
Modeling fructose-load-induced hepatic de-novo lipogenesis by model simplification journal January 2017

Similar Records

Decreasing the Rate of Metabolic Ketone Reduction in the Discovery of a Clinical Acetyl-CoA Carboxylase Inhibitor for the Treatment of Diabetes
Journal Article · Mon Nov 24 23:00:00 EST 2014 · Journal of Medicinal Chemistry · OSTI ID:1191716
Discovery of Small Molecule Isozyme Non-specific Inhibitors of Mammalian Acetyl-CoA Carboxylase 1 and 2
Journal Article · Thu Dec 31 23:00:00 EST 2009 · Bioorganic and Medicinal Chemistry Letters · OSTI ID:1019899
Screening for Dimerization Inhibitors for Bacterial Acetyl CoA Carboxylase
Technical Report · Mon Nov 11 23:00:00 EST 2019 · OSTI ID:1573932

Related Subjects

59 BASIC BIOLOGICAL SCIENCES