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Lithocholic Acid Derivatives as Potent Vitamin D Receptor Agonists

Authors :
Ayana Yoshihara
Keiko Yamamoto
Hiroyuki Kagechika
Aya Tanatani
Nobutoshi Ito
Haru Kawasaki
Harue Sasaki
Nobutaka Numoto
Naoya Hirata
Hiroyuki Masuno
Emiko Kawachi
Yasunari Kanda
Hiroaki Ishida
Source :
Journal of Medicinal Chemistry. 64:516-526
Publication Year :
2020
Publisher :
American Chemical Society (ACS), 2020.

Abstract

Lithocholic acid (2) was identified as a second endogenous ligand of vitamin D receptor (VDR), though its activity is very weak. In this study, we designed novel lithocholic acid derivatives based on the crystal structure of VDR-ligand-binding domain (LBD) bound to 2. Among the synthesized compounds, 6 bearing a 2-hydroxy-2-methylprop-1-yl group instead of the 3-hydroxy group at the 3α-position of 2 showed dramatically increased activity in HL-60 cell differentiation assay, being at least 10 000 times more potent than lithocholic acid (2) and 3 times more potent than 1α,25-dihydroxyvitamin D3 (1). Although the binding affinities of 6 and its epimer 7 were less than that of 1, their transactivation activities were greater than that of 1. X-ray structure analyses of VDR LBD bound to 6 or 7 showed that the binding positions of these compounds in the ligand-binding pocket are similar to that of 1.

Details

ISSN :
15204804 and 00222623
Volume :
64
Database :
OpenAIRE
Journal :
Journal of Medicinal Chemistry
Accession number :
edsair.doi.dedup.....52bf619db2b09df7143c4b0ba3feb210