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Decreasing the rate of metabolic ketone reduction in the discovery of a clinical acetyl-CoA carboxylase inhibitor for the treatment of diabetes.

Griffith DA, Kung DW, Esler WP, Amor PA, Bagley SW, Beysen C, Carvajal-Gonzalez S, Doran SD, Limberakis C, Mathiowetz AM, McPherson K, Price DA, Ravussin E, Sonnenberg GE, Southers JA, Sweet LJ, Turner SM, Vajdos FF
J Med Chem 57 10512-26 (2014)
Cited: 34 times
EuropePMC logo PMID: 25423286

Abstract

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. This demonstration of target engagement validates the use of compound 9 to evaluate the role of DNL in human disease.

Reviews citing this publication (13)

  1. Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol. Xiao C, Dash S, Morgantini C, Hegele RA, Lewis GF. Diabetes 65 1767-1778 (2016)
  2. Metabolic drivers of non-alcoholic fatty liver disease. Bence KK, Birnbaum MJ. Mol Metab 50 101143 (2021)
  3. Lipogenesis inhibitors: therapeutic opportunities and challenges. Batchuluun B, Pinkosky SL, Steinberg GR. Nat Rev Drug Discov 21 283-305 (2022)
  4. Metabolic Targets in Nonalcoholic Fatty Liver Disease. Esler WP, Bence KK. Cell Mol Gastroenterol Hepatol 8 247-267 (2019)
  5. Clinical assessment of hepatic de novo lipogenesis in non-alcoholic fatty liver disease. Paglialunga S, Dehn CA. Lipids Health Dis 15 159 (2016)
  6. Acetyl-CoA Carboxylases and Diseases. Wang Y, Yu W, Li S, Guo D, He J, Wang Y. Front Oncol 12 836058 (2022)
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  9. Photochemical Methods for Peptide Macrocyclisation. Raynal L, Rose NC, Donald JR, Spicer CD. Chemistry 27 69-88 (2021)
  10. Controlling the Burden of COVID-19 by Manipulating Host Metabolism. Miller L, Berber E, Sumbria D, Rouse BT. Viral Immunol 35 24-32 (2022)
  11. The impact of transcription on metabolism in prostate and breast cancers. Poulose N, Mills IG, Steele RE. Endocr Relat Cancer 25 R435-R452 (2018)
  12. Advances and Emerging Therapies in the Treatment of Non-alcoholic Steatohepatitis. Brennan PN, Dillon JF, McCrimmon R. touchREV Endocrinol 18 148-155 (2022)
  13. Pharmacologic inhibition of lipogenesis for the treatment of NAFLD. Esler WP, Cohen DE. J Hepatol 80 362-377 (2024)

Articles citing this publication (21)

  1. Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats. Harriman G, Greenwood J, Bhat S, Huang X, Wang R, Paul D, Tong L, Saha AK, Westlin WF, Kapeller R, Harwood HJ. Proc Natl Acad Sci U S A 113 E1796-805 (2016)
  2. Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: A randomized, double-blind, crossover study. Stiede K, Miao W, Blanchette HS, Beysen C, Harriman G, Harwood HJ, Kelley H, Kapeller R, Schmalbach T, Westlin WF. Hepatology 66 324-334 (2017)
  3. ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials. Calle RA, Amin NB, Carvajal-Gonzalez S, Ross TT, Bergman A, Aggarwal S, Crowley C, Rinaldi A, Mancuso J, Aggarwal N, Somayaji V, Inglot M, Tuthill TA, Kou K, Boucher M, Tesz G, Dullea R, Bence KK, Kim AM, Pfefferkorn JA, Esler WP. Nat Med 27 1836-1848 (2021)
  4. The utilization of spirocyclic scaffolds in novel drug discovery. Zheng YJ, Tice CM. Expert Opin Drug Discov 11 831-834 (2016)
  5. Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data. Sinha S, Thomas D, Chan S, Gao Y, Brunen D, Torabi D, Reinisch A, Hernandez D, Chan A, Rankin EB, Bernards R, Majeti R, Dill DL. Nat Commun 8 15580 (2017)
  6. Acetyl-CoA Carboxylase Inhibition Improves Multiple Dimensions of NASH Pathogenesis in Model Systems. Ross TT, Crowley C, Kelly KL, Rinaldi A, Beebe DA, Lech MP, Martinez RV, Carvajal-Gonzalez S, Boucher M, Hirenallur-Shanthappa D, Morin J, Opsahl AC, Vargas SR, Bence KK, Pfefferkorn JA, Esler WP. Cell Mol Gastroenterol Hepatol 10 829-851 (2020)
  7. Inhibiting both proline biosynthesis and lipogenesis synergistically suppresses tumor growth. Liu M, Wang Y, Yang C, Ruan Y, Bai C, Chu Q, Cui Y, Chen C, Ying G, Li B. J Exp Med 217 e20191226 (2020)
  8. Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models. Jiménez de Oya N, Esler WP, Huard K, El-Kattan AF, Karamanlidis G, Blázquez AB, Ramos-Ibeas P, Escribano-Romero E, Louloudes-Lázaro A, Casas J, Sobrino F, Hoehn K, James DE, Gutiérrez-Adán A, Saiz JC, Martín-Acebes MA. Emerg Microbes Infect 8 624-636 (2019)
  9. Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Liver-Targeting Acetyl-CoA Carboxylase Inhibitor (PF-05221304): A Three-Part Randomized Phase 1 Study. Bergman A, Carvajal-Gonzalez S, Tarabar S, Saxena AR, Esler WP, Amin NB. Clin Pharmacol Drug Dev 9 514-526 (2020)
  10. High Fat Activates O-GlcNAcylation and Affects AMPK/ACC Pathway to Regulate Lipid Metabolism. Pang Y, Xu X, Xiang X, Li Y, Zhao Z, Li J, Gao S, Liu Q, Mai K, Ai Q. Nutrients 13 1740 (2021)
  11. Dose-dependent quantitative effects of acute fructose administration on hepatic de novo lipogenesis in healthy humans. Beysen C, Ruddy M, Stoch A, Mixson L, Rosko K, Riiff T, Turner SM, Hellerstein MK, Murphy EJ. Am J Physiol Endocrinol Metab 315 E126-E132 (2018)
  12. De novo lipogenesis is essential for platelet production in humans. Kelly KL, Reagan WJ, Sonnenberg GE, Clasquin M, Hales K, Asano S, Amor PA, Carvajal-Gonzalez S, Shirai N, Matthews MD, Li KW, Hellerstein MK, Vera NB, Ross TT, Cappon G, Bergman A, Buckeridge C, Sun Z, Qejvanaj EZ, Schmahai T, Beebe D, Pfefferkorn JA, Esler WP. Nat Metab 2 1163-1178 (2020)
  13. A combined drug discovery strategy based on machine learning and molecular docking. Zhang Y, Wang Y, Zhou W, Fan Y, Zhao J, Zhu L, Lu S, Lu T, Chen Y, Liu H. Chem Biol Drug Des 93 685-699 (2019)
  14. WZ66, a novel acetyl-CoA carboxylase inhibitor, alleviates nonalcoholic steatohepatitis (NASH) in mice. Gao YS, Qian MY, Wei QQ, Duan XB, Wang SL, Hu HY, Liu J, Pan CY, Zhang SQ, Qi LW, Zhou JP, Zhang HB, Wang LR. Acta Pharmacol Sin 41 336-347 (2020)
  15. 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) prevents high fat diet-induced insulin resistance via maintenance of hepatic lipid homeostasis. Mohan H, Brandt SL, Kim JH, Wong F, Lai M, Prentice KJ, Al Rijjal D, Magomedova L, Batchuluun B, Burdett E, Bhattacharjee A, Cummins CL, Belsham DD, Cox B, Liu Y, Wheeler MB. Diabetes Obes Metab 21 61-72 (2019)
  16. Letter Activity and structure of human acetyl-CoA carboxylase targeted by a specific inhibitor. Jang S, Gornicki P, Marjanovic J, Bass E, P Iurcotta T, Rodriguez P, Austin J, Haselkorn R. FEBS Lett 592 2048-2058 (2018)
  17. Acetyl-CoA Carboxylase Inhibitor CP640.186 Increases Tubulin Acetylation and Impairs Thrombin-Induced Platelet Aggregation. Octave M, Pirotton L, Ginion A, Robaux V, Lepropre S, Ambroise J, Bouzin C, Guigas B, Giera M, Foretz M, Bertrand L, Beauloye C, Horman S. Int J Mol Sci 22 13129 (2021)
  18. Modeling fructose-load-induced hepatic de-novo lipogenesis by model simplification. Allen RJ, Musante CJ. Gene Regul Syst Bio 11 1177625017690133 (2017)
  19. Role of AMPK-SREBP Signaling in Regulating Fatty Acid Binding-4 (FABP4) Expression following Ethanol Metabolism. Attal N, Marrero E, Thompson KJ, McKillop IH. Biology (Basel) 11 1613 (2022)
  20. Virtual Screening Strategy Combined Bayesian Classification Model, Molecular Docking for Acetyl-CoA Carboxylases Inhibitors. Zhou WN, Zhang YM, Qiao X, Pan J, Yin LF, Zhu L, Zhao JN, Lu S, Lu T, Chen YD, Liu HC. Curr Comput Aided Drug Des 15 193-205 (2019)
  21. Synthesis and biological evaluation of 4-phenoxy-phenyl isoxazoles as novel acetyl-CoA carboxylase inhibitors. Wu X, Yu Y, Huang T. J Enzyme Inhib Med Chem 36 1236-1247 (2021)


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