Bile acid derivatives as ligands of the farnesoid X receptor. Synthesis, evaluation, and structure-activity relationship of a series of body and side chain modified analogues of chenodeoxycholic acid.
The farnesoid X receptor (FXR) is activated by endogenous bile acids (BAs) and plays a variety of physiological roles related to modulation of gene transcription. In particular, FXR positively regulates the cholesterol catabolism while feedback inhibits the BA synthesis by repressing the expression of the CYP7A and CYP8B genes. We have previously shown that 6alpha-ethyl-CDCA (6ECDCA) is a potent and selective FXR agonist. In this paper we report an extensive structure-activity relationship for a series of synthetic bile acids. Our results indicate that the 6alpha position plays a fundamental role in determining affinity and that the side chain of BA is amenable to a variety of chemical modification. Although none of the new derivatives is more potent than 6ECDCA, we show here that a wide variability in efficacy, from full agonists to partial antagonists, can be obtained.
Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo, 1, 06123 Perugia, Italy. rp@unipg.it
Roberto
R
Pellicciari
Gabriele
G
Costantino
Emidio
E
Camaioni
Bahman M
BM
Sadeghpour
Antonio
A
Entrena
Timothy M
TM
Willson
Stefano
S
Fiorucci
Carlo
C
Clerici
Antimo
A
Gioiello
D001647:Bile Acids and Salts / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated