SIOC 中文
CJOG
Adv search

Chinese Journal of Organic Chemistry >

2024 , Vol. 44 >Issue 11: 3476 - 3489

DOI: https://doi.org/10.6023/cjoc202405036

ARTICLE

Discovery of Alkyl Conjugated Diene Diacids as Novel ACLY Inhibitors

  • Tingting Cheng ,
  • Gaolei Song ,
  • Long Cheng ,
  • Fan Wang ,
  • Xinyu Sun ,
  • Zhifu Xie ,
  • Mei Zhang ,
  • Yangming Zhang ,
  • Jingya Li ,
  • Fajun Nan
Expand
  • a State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203
    b University of Chinese Academy of Sciences, Beijing 100049
    c School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023
    d Burgeon Therapeutics Co., Ltd, Shanghai 201203
†The authors contributed equally to this work.
*Corresponding author. E-mail:;

Received date: 2024-05-27

  Revised date: 2024-05-30

  Online published: 2024-07-15

Supported by

National Natural Science Foundation of China(82170872); Medical Guidance Project of Shanghai Science and Technology Commission(20S11903400); Natural Science Foundation of Shanghai Science and Technology Innovation Action Plan(21ZR1475300)

Fold

Abstract

Adenosine triphosphate (ATP)-citrate lyase (ACLY) converts cytosolic citrate from the tricarboxylic acid cycle (TCA cycle) into acetyl coenzyme A (acetyl-CoA), which is a building block for cholesterol and fatty acid synthesis. Abnormally high expression of ACLY is associated with multiple metabolic diseases including dyslipidemia, atherosclerosis and non-alcoholic steatohepatitis (NASH), making ACLY an appealing target. In previous work, 326Eb was discovered, featuring an alkenyl dicarboxylic acid scaffold as a novel ACLY inhibitor. 326E can be potentially used to treat hypercholesterolemia and is currently undergoing phase II clinical trials. In this study, a series of diacids containing conjugated diene were developed based on impurities in manufacturing process of 326E in good manufacturing practice of medical products (GMP) condition, which represented a unique structural type different from known ACLY inhibitors. Among synthesized all eight possible isomers, compounds 43ZZ and 52EE exhibited significant inhibitory effect on de novo lipogenesis and gluconeogenesis in vitro and 43ZZ showed favorable pharmacokinetics. Furthermore, oral administration of 43ZZ and 52EE demonstrated a marked reduction of hepatic lipogenesis, along with lowered plasma levels of triglyceride and cholesterol, thereby confirming that these diene diacids as novel ACLY inhibitors have therapeutic potential for hyperlipidemia.

Key words： metabolic diseases; ATP-citrate lyase (ACLY); lipogenesis; ACLY inhibitors; dienyldicarboxylic acid

Cite this article

Tingting Cheng , Gaolei Song , Long Cheng , Fan Wang , Xinyu Sun , Zhifu Xie , Mei Zhang , Yangming Zhang , Jingya Li , Fajun Nan . Discovery of Alkyl Conjugated Diene Diacids as Novel ACLY Inhibitors[J]. Chinese Journal of Organic Chemistry, 2024 , 44(11) : 3476 -3489 . DOI: 10.6023/cjoc202405036

References

[1]
Moore M. C.; Coate K. C.; Winnick J. J.; An Z.; Cherrington A. D. Adv Nutr. 2012, 3, 286.
[2]
Petersen M. C.; Vatner D. F.; Shulman G. I. Nat. Rev. Endocrinol. 2017, 13, 572.
[3]
Tan M.; Mosaoa R.; Graham G. T.; Kasprzyk-Pawelec A.; Gadre S.; Parasido E.; Catalina-Rodriguez O.; Foley P.; Giaccone G.; Cheema A.; Kallakury B.; Albanese C.; Yi C.; Avantaggiati M. L. Cell Death Differ. 2020, 27, 2143.
[4]
Wei X.; Schultz K.; Bazilevsky G. A.; Vogt A.; Marmorstein R. Nat. Struct. Mol. Biol. 2020, 27, 33.
[5]
Srere P. A. J. Biol. Chem. 1959, 234, 2544.
[6]
Lau F. D.; Giugliano R. P. JAMA Cardiol. 2023, 8, 879.
[7]
Zaidi N.; Swinnen J. V.; Smans K. Cancer Res. 2012, 72, 3709.
[8]
Granchi C. Eur. J. Med. Chem. 2018, 157, 1276.
[9]
Pinkosky S. L.; Groot P. H. E.; Lalwani N. D. Trends Mol. Med. 2017, 23, 1047.
[10]
Feng X.-J.; Zhang L.; Xu S.-W.; Shen A.-Z. Prog. Lipid Res. 2020, 77, 101006.
[11]
Morrow M. R.; Batchuluun B.; Wu J.; Ahmadi E.; Leroux J. M.; Mohammadi-Shemirani P.; Desjardins E. M.; Wang Z.; Tsakiridis E. E.; Lavoie D. C. T.; Reihani A.; Smith B. K.; Kwiecien J. M.; Lally J. S. V.; Nero T. L.; Parker M. W.; Ask K.; Scott J. W.; Jiang L.; Paré G.; Pinkosky S. L.; Steinberg G. R. Cell Metab. 2022, 34, 919.
[12]
Liang J.-J.; Zhou X.-F.; Long H.; Li C.-Y.; Wei J.; Yu X.-Q.; Guo Z.-Y.; Zhou Y.-Q.; Deng Z.-S. Bioorg. Chem. 2024, 142, 106933.
[13]
Li J.-J.; Wang H.; Tino J. A.; Robl J. A, Herpin T. F.; Lawrenc R. M.; Biller S.; Jamil H.; Ponticiello R.; Chen L.; Chu C.-H.; Flynn N.; Cheng D.; Zhao R.; Chen B.; Schnur D.; Obermeier M. T.; Sasseville V.; Padmanabha R.; Pike K.; Harrity T. Bioorg. Med. Chem. Lett. 2007, 17, 3208.
[14]
Wei J.; Leit S.; Kuai J.; Therrien E.; Rafi S.; Harwood H. J.; Jr, DeLaBarre B.; Tong L. Nature 2019, 568, 566.
[15]
Gribble A. D.; Ife R. J.; Shaw A.; McNair D.; Novelli C. E.; Bakewell S.; Shah V. P.; Dolle R. E.; Groot P. H.; Pearce N.; Yates J.; Tew D.; Boyd H.; Ashman S.; Eggleston D. S.; Haltiwanger R. C.; Okafo G. J. Med. Chem. 1998, 41, 3582.
[16]
Ray K. K.; Bays H. E.; Catapano A. L.; Lalwani N. D.; Bloedon L. T.; Sterling L. R.; Robinson P. L.; Ballantyne C. M.; Trial C. H. N. Engl. J. Med. 2019, 380, 1022.
[17]
Goldberg A. C.; Leiter L. A.; Stroes E. S. G.; Baum S. J.; Hanselman J. C.; Bloedon L. T.; Lalwani N. D.; Patel P. M.; Zhao X.; Duell P. B. JAMA 2019, 322, 1780.
[18]
Pinkosky S. L.; Newton R. S.; Day E. A.; Ford R. J.; Lhotak S.; Austin R. C.; Birch C. M.; Smith B. K.; Filippov S.; Groot P. H. E.; Steinberg G. R.; Lalwani N. D. Nat. Commun. 2016, 7, 13457.
[19]
Xie Z.-F.; Zhang M.; Song Q.; Cheng L.; Zhang X.-W.; Song G.-L.; Sun X.-Y.; Gu M.; Zhou C.-D.; Zhang Y.-M.; Zhu K.-X.; Yin J.-P.; Chen X.-Y.; Li J.-Y.; Nan F.-J. Acta. Pharm. Sin. B 2023, 13, 739.
[20]
Song G.-L.; Cao L.; Zhang M.; Yang Y.-R.; Ma J.; Xie Z.-F.; Li J.-Y.; Nan F.-J. Chin. J. Chem. 2022, 40, 2663.
[21]
Wang G.-W.; Mohan S.; Negishi E. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 11344.
[22]
Wang Y. D.; Kimball G.; Prashad A. S.; Wang Y. Tetrahedron Lett. 2005, 46, 8777.
[23]
Ren G.-B.; Wu Y.-K. Tetrahedron 2008, 64, 4408.
[24]
Molander G. A.; Trice S. L.; Kennedy S. M. J. Org. Chem. 2012, 77, 8678.
[25]
Suh Y. G.; Min K. H.; Lee Y. S.; Seo S. Y.; Kim S. H.; Park H. J. Tetrahedron Lett. 2002, 43, 3825.
[26]
Zhao S.; Jang C.; Liu J.; Uehara K.; Gilbert M.; Izzo L.; Zeng X.; Trefely S.; Fernandez S.; Carrer A.; Miller K. D.; Schug Z. T.; Snyder N. W.; Gade T. P.; Titchenell P. M.; Rabinowitz J. D.; Wellen K. E. Nature 2020, 579, 586.
[27]
Softic S.; Cohen D. E.; Kahn E. R. Dig. Dis. Sci. 2016, 61, 1282.
[28]
Pinkosky S. L.; Filippov S.; Srivastava R. A.; Hanselman J. C.; Bradshaw C. D.; Hurley T. R.; Cramer C. T.; Spahr M. A.; Brant A. F.; Houghton J. L.; Baker C.; Naples M.; Adeli K.; Newton R. S. J. Lipid Res. 2013, 54, 131.
[29]
Li W.-C.; Ralphs K. L.; Tosh D. Methods Mol. Biol. 2010, 633, 185.
Options
Outlines

/

〈 〉