Lathyrane Diterpenoids as Novel hPXR Agonists: Isolation, Structural Modification, and Structure-Activity Relationships.

Pregnane X receptor (PXR) that orchestrates the intricate network of xeno- and endobiotic metabolism is considered as a promising therapeutic target for cholestasis. In this study, the human PXR (hPXR) agonistic bioassay-guided isolation of Euphorbia lathyris followed by the structural modification led to the construction of a lathyrane diterpenoid library (1-34). Subsequent assay of this library led to the identification of a series of potent hPXR agonists, showing better efficacy than that of typical hPXR agonist, rifampicin. The most active compound, 8, could dose-dependently activate hPXR at micromolar concentrations and significantly up-regulate the expressions of PXR downstream genes CYP3A4, CYP2B6, and MDR1. The structure-activity relationships (SARs) studied in combination with molecular modeling suggested that acyloxy at C-7 and the presence of 14-carbonyl were essential to the activity. These findings suggested that lathyrane diterpenoids could serve as a new type of hPXR agonist for future anticholestasis drug development.