SIOC 中文
CJOG
Adv search

Chinese Journal of Organic Chemistry >

2023 , Vol. 43 >Issue 2: 636 - 645

DOI: https://doi.org/10.6023/cjoc202207001

Design, Synthesis and Biological Evaluation of FABP4/5 Inhibitors Based on Quinoline Scaffold

  • Jianfei Gao ,
  • Shunyi Li ,
  • Yulong He ,
  • Yingxia Li ,
  • Heyao Wang ,
  • Erfang Huang ,
  • Chun Hu
Expand
  • a Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110015
    b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203
    c School of Pharmacy, Fudan University, Shanghai 201203
†(The authors contributed equally to this work).
* Corresponding authors. E-mail: ;
* Corresponding authors. E-mail: ;

Received date: 2022-07-02

  Revised date: 2022-09-14

  Online published: 2022-11-08

Supported by

National Natural Science Foundation of China(21342006); Program for Innovative Research Team of the Ministry of Education(IRT_14R36)

Fold

Abstract

Taking the dual FABP 4/5 inhibitor RO6806051 and FABP4 inhibitor XU17 as the lead compounds, twenty new quinoline derivatives as dual FABP4/5 inhibitors were designed and synthesized according to the reported RO6806051/FABP5 crystal complex and XU17/FABP4 crystal complex, then confirmed by 1H NMR, 13C NMR and high-resolution mass spectra (HRMS). All the target compounds were evaluated for their inhibitory activity against FABP4 and FABP5 via the 8-anilino- naphthalene-1-sulfonic acid (1,8-ANS) displacement assay. The results showed that the target compound 2-(2-(6-chloro- 4-(2-chlorophenyl)quinolin-2-yl)phenyl)acetic acid (11a) exhibited strong inhibitory activity against FABP4 (IC50: 4.50 μmol/L) and FABP5 (IC50: 3.90 μmol/L).

Key words： FABP4/5 inhibitors; fusion strategy; quinoline; synthesis

Cite this article

Jianfei Gao , Shunyi Li , Yulong He , Yingxia Li , Heyao Wang , Erfang Huang , Chun Hu . Design, Synthesis and Biological Evaluation of FABP4/5 Inhibitors Based on Quinoline Scaffold[J]. Chinese Journal of Organic Chemistry, 2023 , 43(2) : 636 -645 . DOI: 10.6023/cjoc202207001

References

[1]
Judith, S.; Lindsay, M. J. Lipid Res. 2009, 50, S126.
[2]
Coe, N. R.; Bernlohr, D. A. Biochim. Biophys. Acta, Lipids Lipid Metab. 1998, 1391, 287.
[3]
Furuhashi, M.; Hotamisligil, G. S. Nat. Rev. Drug Discovery 2008, 7, 489.
[4]
Hotamisligil, G. S.; Bernlohr, D. A. Nat. Rev. Endocrinol. 2015, 11, 592.
[5]
Ockner, R. K; Manning, J. A.; Poppenhausen, R., B.; Ho, W. K. Science 1972, 177, 56.
[6]
Storch, J.; Thumser, A. E. J. Biol. Chem. 2010, 285, 32679.
[7]
Liu, R. Z.; Li, X.; Godbout, R. Genomics 2008, 92, 436.
[8]
Hotamisligil, G. S. Nature 2006, 444, 860.
[9]
Saltiel, A. R.; Kahn, C. R. Nature 2001, 414, 799.
[10]
Hunt, C. R.; Ro, J. H.; Dobson, D. E.; Min, H. Y. Proc. Natl Acad. Sci. U. S. A. 1996, 83, 3786.
[11]
Ishimura, S.; Furuhashi, M.; Watanabe, Y.; Hoshina, K.; Fuseya, T.; Mita, T.; Okazaki, Y.; Koyama, M.; Tanaka, M.; Akasaka, H.; Ohnishi, H.; Yoshida, H.; Saitoh, S.; Miura, T. PLoS One 2013, 8, e81318.
[12]
Xu, A.; Wang, Y.; Xu, J. Y.; Stejskal, D.; Tam, S.; Zhang, J.; Wat, N. M.; Wong, W. K.; Lam, K. S. Clin. Chem. 2006, 52, 405.
[13]
Xu, A.; Tso, A. W.; Cheung, B. M. Circulation 2007, 115, 1537.
[14]
Yeung, D. C.; Xu, A.; Cheung, C. W.; Wat, N. M.; Yau, M. H.; Fong, C. H.; Chau, M. T.; Lam, K. S. Arterioscler. Thromb. Vasc. Biol. 2007, 27, 1796.
[15]
Rolph, M. S.; Young, T. R.; Shum, B. O. J. Immunol. 2006, 177, 7794.
[16]
Esteves, A.; Ehrlich, R. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 2006, 142, 262.
[17]
Maeda, K.; Uysal, K. T.; Makowski, L.; Gorgun, C. Z.; Atsumi, G.; Parker, R. A.; Bruning, J.; Hertzel, A. V.; Bernlohr, D. A.; Hotamisligil, G. S. Diabetes 2003, 52, 300.
[18]
Furuhashi, M.; Ogura, M.; Matsumoto, M.; Yuda, S.; Muranaka, A.; Kawamukai, M.; Omori, A.; Tanaka, M. Moniwa, N.; Ohnishi, H.; Saitoh, S.; Harada-Shiba, M.: Shimamoto, K.; Miura, T. Sci. Rep. 2017, 7, 217.
[19]
He, Y. L.; Chen, M. T.; Wang, T.; Zhang, M. M.; Li, Y. X.; Wang, H. Y.; Ding, N. Eur. J. Med. Chem. 2021, 224, 113720.
[20]
Furuhashi, M.; Tuncman, G.; G?rgün, C. Z.; Makowski, L.; Atsumi, G.; Vaillancourt, E.; Kono, K.; Babaev, V. R.; Fazio, S.; Linton, M. F.; Sulsky, R.; Robl, J. A.; Parker, R. A.; Hotamisligil, G. S. Nature 2007, 447, 959.
[21]
Su, H. X.; Zou, Y.; Chen, G. F.; Dou, H. X.; Xie, H.; Yuan, X. J.; Zhang, X. L.; Zhang, N.; Li, M. J.; Xu, Y. C. J. Med. Chem. 2020, 63, 4090.
[22]
Kuhne, H.; Obst-Sander, U.; Kuhn, B.; Conte, A.; Ceccarelli, S. M.; Neidhart, W.; Rudolph, M. G.; Ottaviani, G.; Gasser, R.; So, S. S.; Li, S.; Zhang, X.; Gao, L.; Myers, M. Bioorg. Med. Chem. Lett. 2016, 26, 5092.
[23]
Lan, H.; Cheng, C. C.; Kowalski, T. G.; Pang, L.; Shan, L.; Chuang, C. C.; Jackson, J.; Rojas-Triana, A.; Bober, L.; Liu, L.; Voigt, J.; Orth, P.; Yang, X.; Shipps, G. W. Jr.; Hedrick, J. A. Lipid Res. 2011, 52, 646.
Options
Outlines

/

〈 〉