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

• Published in: European journal of medicinal chemistry Vol. 245; no. Pt 1; pp. 114886 - 114900
• Main Authors: Zhang, Na, Fan, Tianyun, Zhao, Liping, Li, Yiming, Bao, Yunyang, Ma, Xican, Mei, Yuheng, Wang, Yanxiang, Liu, Yonghua, Deng, Hongbin, Li, Yinghong, He, Hongwei, Song, Danqing
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.01.2023; Elsevier
• Subjects: Animals; Antifibrotic Agents - chemistry; Antifibrotic Agents - pharmacology; Antifibrotic Agents - therapeutic use; Berberine Alkaloids - chemistry; Berberine Alkaloids - pharmacology; Berberine Alkaloids - therapeutic use; Chemistry, Medicinal; Choline-deficient; Farnesoid X receptor; High-fat diet; l-amino acid-Defined; Life Sciences & Biomedicine; Liver - drug effects; Liver - metabolism; Liver Cirrhosis - metabolism; Mice; Mice, Inbred C57BL; NASH; Non-alcoholic Fatty Liver Disease - drug therapy; Palmatine analogues; Pharmacology & Pharmacy; Rats; Science & Technology; Structure−activity relationship; Farnesoid X receptor; Palmatine analogues; Choline-deficient; High-fat diet; l-amino acid-Defined; NASH; Structure−activity relationship; FIBROSIS; Structure-activity relationship; L-amino acid-Defined
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114886

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. [Display omitted] •61 palmatine analogues are prepared and evaluated for their antifibrogenic effects.•3a inhibits COL1A1 with IC50 value of 8.19 μmol/L and SI value of 8.59.•3a exerts reasonable druglike property with high safety and metabolic stability.•3a ameliorates CDAHFD and BDL-induced liver injury in vivo by activating FXR.