Discovery and development of palmatine analogues as anti-NASH agents by activating farnesoid X receptor (FXR)

  • Eur J Med Chem. 2023 Jan 5;245(Pt 1):114886. doi: 10.1016/j.ejmech.2022.114886.
Na Zhang  1 ,  Tianyun Fan  2 ,  Liping Zhao  1 ,  Yiming Li  1 ,  Yunyang Bao  1 ,  Xican Ma  1 ,  Yuheng Mei  1 ,  Yanxiang Wang  1 ,  Yonghua Liu  1 ,  Hongbin Deng  1 ,  Yinghong Li  3 ,  Hongwei He  4 ,  Danqing Song  1
Affiliations
  • 1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
  • 2. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
  • 3. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
  • 4. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
PMID: 36347091 DOI: 10.1016/j.ejmech.2022.114886
Abstract

Sixty-one palmatine (PMT) derivatives, of which twenty-eight were new, were synthesized and evaluated for their anti-fibrogenic activities via Collagen type I α 1 (COL1A1)-promoter based luciferase model in LX-2 cells, taking 2,3,10-trimethoxy-9-p-isopropyloxyprotopalmatine bromide (1) as the lead. Among them, compound 3a exerted the highest potency with the IC50 value of 8.19 μmol/L and SI value of 8.59, and reduced the expressions of multiple fibrogenic biomarkers, including COL1A1, TGF-β1, α-SMA and TIMP1 in a dose-dependent manner. In addition, it significantly reduced liver steatosis and inflammation, and especially attenuated the degree of liver fibrosis in choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD)-induced NASH mice model in vivo. Mechanism study indicated that it significantly ameliorated liver injury by activating farnesoid X receptor (FXR). BDL-induced fibrosis rats model further verified its liver-protective and anti-fibrosis activities. Therefore, PMT derivatives constituted a new family of non-steroidal FXR agonists as anti-NASH candidates, with the advantage of good safety profile, and are worthy for further investigation.

Keywords
Choline-deficient; Farnesoid X receptor; High-fat diet; NASH; Palmatine analogues; Structure−activity relationship; l-amino acid-Defined.
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