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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 Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); Pfizer Inc.; National Institutes of Health (NIH)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1191716
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)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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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
Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase journal January 2012
Synthesis of 7-Oxo-dihydrospiro[indazole-5,4′-piperidine] Acetyl-CoA Carboxylase Inhibitors journal January 2012
De novo lipogenesis in humans: metabolic and regulatory aspects journal April 1999
Stimulation of Fat Oxidation, but no Sustained Reduction of Hepatic Lipids by Prolonged Pharmacological Inhibition of Acetyl CoA Carboxylase journal August 2011
Structure-guided Inhibitor Design for Human Acetyl-coenzyme A Carboxylase by Interspecies Active Site Conversion journal December 2011
Overview of the CCP 4 suite and current developments journal March 2011
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Soraphen, an inhibitor of the acetyl-CoA carboxylase system, improves peripheral insulin sensitivity in mice fed a high-fat diet journal October 2009
Liver fat and lipid oxidation in humans journal October 2009
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Disordered Lipid Metabolism and the Pathogenesis of Insulin Resistance journal April 2007
Acetyl-coenzyme A carboxylases: Versatile targets for drug discovery journal January 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
Lipid-induced insulin resistance: unravelling the mechanism journal June 2010
Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2 journal April 2010
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
Crystal Structure of the Carboxyltransferase Domain of Acetyl-Coenzyme A Carboxylase in Complex with CP-640186 journal September 2004
Complementary α-alkylation approaches for a sterically hindered spiro[pyrazolopyranpiperidine]ketone journal May 2012
ElogD o ct :  A Tool for Lipophilicity Determination in Drug Discovery. 2. Basic and Neutral Compounds journal July 2001
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
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
Identification and Synthesis of Novel Inhibitors of Acetyl-CoA Carboxylase with in Vitro and in Vivo Efficacy on Fat Oxidation journal December 2010
Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase journal January 2012
Piperazine Oxadiazole Inhibitors of Acetyl-CoA Carboxylase journal December 2013
Synthesis of 7-Oxo-dihydrospiro[indazole-5,4′-piperidine] Acetyl-CoA Carboxylase Inhibitors journal January 2012
De novo lipogenesis in humans: metabolic and regulatory aspects journal April 1999
Stimulation of Fat Oxidation, but no Sustained Reduction of Hepatic Lipids by Prolonged Pharmacological Inhibition of Acetyl CoA Carboxylase journal August 2011
Structure-guided Inhibitor Design for Human Acetyl-coenzyme A Carboxylase by Interspecies Active Site Conversion journal December 2011
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
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Scaling and assessment of data quality journal December 2005
XDS journal January 2010
Overview of the CCP 4 suite and current developments journal March 2011
Data processing and analysis with the autoPROC toolbox journal March 2011
Refinement of Macromolecular Structures by the Maximum-Likelihood Method journal May 1997
Soraphen, an inhibitor of the acetyl-CoA carboxylase system, improves peripheral insulin sensitivity in mice fed a high-fat diet journal October 2009
Liver fat and lipid oxidation in humans journal October 2009
Malonyl-CoA, a Key Signaling Molecule in Mammalian Cells journal August 2008
Disordered Lipid Metabolism and the Pathogenesis of Insulin Resistance journal April 2007

Cited By (18)

Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: A randomized, double-blind, crossover study journal July 2017
Metabolic Targets in Nonalcoholic Fatty Liver Disease journal January 2019
Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data journal May 2017
Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models journal January 2019
Modeling fructose-load-induced hepatic de-novo lipogenesis by model simplification journal January 2017
Clinical assessment of hepatic de novo lipogenesis in non-alcoholic fatty liver disease journal September 2016
Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: A randomized, double-blind, crossover study journal July 2017
Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data journal May 2017
The intriguing chemistry and biology of soraphens journal January 2019
Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats journal March 2016
The utilization of spirocyclic scaffolds in novel drug discovery journal June 2016
Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models journal January 2019
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
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
Human sebum requires de novo lipogenesis, which is increased in acne vulgaris and suppressed by acetyl-CoA carboxylase inhibition journal May 2019
Dose-dependent quantitative effects of acute fructose administration on hepatic de novo lipogenesis in healthy humans journal July 2018
Clinical assessment of hepatic de novo lipogenesis in non-alcoholic fatty liver disease journal September 2016

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