Lithocholic Acid Derivatives as Potent Vitamin D Receptor Agonists.
J Med Chem
; 64(1): 516-526, 2021 01 14.
Article
de En
| MEDLINE
| ID: mdl-33369416
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 10â¯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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Récepteur calcitriol
/
Acide lithocholique
Limites:
Animals
/
Humans
Langue:
En
Journal:
J Med Chem
Sujet du journal:
QUIMICA
Année:
2021
Type de document:
Article
Pays d'affiliation:
Japon