Correlation Engine 2.0
Clear Search sequence regions

  • benzothiazoles (2)
  • bile acid (1)
  • cellular (1)
  • FXR (14)
  • gene (2)
  • gw4064 (2)
  • Hep (1)
  • homeostasis (1)
  • humans (1)
  • lipid homeostasis (1)
  • lipids (2)
  • mice (3)
  • phase (1)
  • receptors (3)
  • sas (1)
  • urea (1)
  • Sizes of these terms reflect their relevance to your search.

    Farnesoid X receptor (FXR) agonists are emerging as potential therapeutics for the treatment of various metabolic diseases, as they display multiple effects on bile acid, lipid, and glucose homeostasis. Although the steroidal obeticholic acid, a full FXR agonist, was recently approved, several side effects probably due to insufficient pharmacological selectivity impede its further clinical application. Activating FXR in a partial manner is therefore crucial in the development of novel FXR modulators. Our efforts focusing on isoxazole-type FXR agonists, common nonsteroidal agonists for FXR, led to the discovery a series of novel FXR agonists bearing aryl urea moieties through structural simplification of LJN452 (phase 2). Encouragingly, compound 11k was discovered as a potent FXR agonist which exhibited similar FXR agonism potency but lower maximum efficacy compared to full agonists GW4064 and LJN452 in cell-based FXR transactivation assay. Extensive in vitro evaluation further confirmed partial efficacy of 11k in cellular FXR-dependent gene modulation, and revealed its lipid-reducing activity. More importantly, orally administration of 11k in mice exhibited desirable pharmacokinetic characters resulting in promising in vivo FXR agonistic activity. Copyright © 2020 Elsevier Masson SAS. All rights reserved.


    Guoshun Luo, Xin Lin, Zhenbang Li, Maoxu Xiao, Xinyu Li, Dayong Zhang, Hua Xiang. Structure-guided modification of isoxazole-type FXR agonists: Identification of a potent and orally bioavailable FXR modulator. European journal of medicinal chemistry. 2021 Jan 01;209:112910

    Expand section icon Mesh Tags

    Expand section icon Substances

    PMID: 33049605

    View Full Text