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
- 23 July 2004
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 47 (18), 4559-4569
- https://doi.org/10.1021/jm049904b
Abstract
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.Keywords
This publication has 29 references indexed in Scilit:
- An Expedient Synthesis of 6α-Fluoroursodeoxycholic AcidOrganic Process Research & Development, 2002
- Nuclear Receptors and Lipid Physiology: Opening the X-FilesScience, 2001
- Cyclobutane Quisqualic Acid Analogues as Selective mGluR5a Metabotropic Glutamic Acid Receptor LigandsJournal of Medicinal Chemistry, 1999
- Metabolism, pharmacokinetics, and activity of a new 6-fluoro analogue of ursodeoxycholic acid in rats and hamstersGastroenterology, 1995
- Synthesis of 6-hydroxylated bile acids and identification of 3.ALPHA.,6.ALPHA.,7.ALPHA.,12.ALPHA.-tetrahydroxy-5.BETA.-cholan-24-oic acid in human meconium and neonatal urine.CHEMICAL & PHARMACEUTICAL BULLETIN, 1989
- Stereoselectivity in reduction of steroidal 7-ketones.CHEMICAL & PHARMACEUTICAL BULLETIN, 1987
- Synthesis of 3β‐Hydroxy[21‐14C]‐5β‐pregn‐8(14)‐en‐20‐one from Chenodeoxycholic AcidHelvetica Chimica Acta, 1986
- Bile acids with cyclopropane-containing side chain. 2. Synthesis and properties of 3.alpha.,7.beta.-dihydroxy-22,23-methylene-5.beta.-cholan-24-oic acid (2-sulfoethyl)amideJournal of Medicinal Chemistry, 1985
- The Preparation of 1,5,6-Trimethylbenzotriazole and 1-Methyl-V-triazole-4,5-dicarboxylic AcidJournal of the American Chemical Society, 1954
- Preparation and NaBH4 Reduction of 7-Ketocholanic AcidJournal of the American Chemical Society, 1954