Discovery of 9,11-Seco-Cholesterol Derivatives as Novel FXR Antagonists

Jia-Xu Zhou; Cui-Na Li; Ya-Meng Liu; Su-Qin Lin; Ying Wang; Cen Xie; Fa-Jun Nan

doi:10.1021/acsomega.2c01567

Discovery of 9,11-Seco-Cholesterol Derivatives as Novel FXR Antagonists

ACS Omega. 2022 May 12;7(20):17401-17405. doi: 10.1021/acsomega.2c01567. eCollection 2022 May 24.

Authors

Jia-Xu Zhou^{1

2}, Cui-Na Li², Ya-Meng Liu², Su-Qin Lin³, Ying Wang², Cen Xie², Fa-Jun Nan^{1

2

4}

Affiliations

¹ University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, People's Republic of China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.
³ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, People's Republic of China.
⁴ Drug Discovery Shandong Laboratory, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, People's Republic of China.

Abstract

The farnesoid X receptor (FXR) plays an important role in the regulation of bile acid, lipid, and glucose homeostasis. Recent findings have shown that the inhibition of FXR is beneficial to improvement of related metabolic diseases and cholestasis. In the present work, 9,11-seco-cholesterol derivatives were designed and synthesized by cleaving the C ring of cholesterol and were identified as novel structures of FXR antagonists. Compound 9a displayed the best FXR antagonistic activity at the cellular level (IC₅₀ = 4.6 μM) and decreased the expression of the target genes of FXR in vivo.