Conformationally constrained farnesoid X receptor (FXR) agonists: Alternative replacements of the stilbene

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 20; pp. 6154 - 6160
• Main Authors: Akwabi-Ameyaw, Adwoa, Caravella, Justin A., Chen, Lihong, Creech, Katrina L., Deaton, David N., Madauss, Kevin P., Marr, Harry B., Miller, Aaron B., Navas, Frank, Parks, Derek J., Spearing, Paul K., Todd, Dan, Williams, Shawn P., Wisely, G. Bruce
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.10.2011; Elsevier
• Subjects: agonists; Amino Acid Sequence; Animals; Bile acid receptor; Biological and medical sciences; carboxylic acids; Cell Line; chemical structure; Farnesoid X receptor; FXR; FXR X-ray co-crystal structure; General and cellular metabolism. Vitamins; GSK2324; GSK8062; GW 4064; Humans; Isoxazoles - chemistry; Isoxazoles - pharmacology; Medical sciences; Molecular Conformation; Molecular Sequence Data; NR1H4; Nuclear receptor modulator; Pharmacology. Drug treatments; receptors; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - metabolism; stilbenes; Stilbenes - chemistry; Stilbenes - pharmacology; Farnesoid X receptor; FXR X-ray co-crystal structure; FXR; GW 4064; Bile acid receptor; GSK8062; GSK2324; NR1H4; Nuclear receptor modulator; Steroid; Agonist; Nuclear receptor; Intravenous administration; Isoxazole derivatives; Rat; Benzothiophene derivatives; Structure activity relation; Bile acid; Chlorine Organic compounds; Cocrystal; Modulation; Chemical synthesis; Molecular rigidity; Rodentia; Oral administration; Quinoline derivatives; Steric hindrance; In vitro; Vertebrata; Mammalia; Benzimidazole derivatives; Animal; Benzofuran derivatives; Indole derivatives; Pharmacokinetics; Crystalline structure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.08.034

To further explore the optimum placement of the acid moiety in conformationally constrained analogs of GW 4064 1a, a series of stilbene replacements were prepared. The benzothiophene 1f and the indole 1g display the optimal orientation of the carboxylate for enhanced FXR agonist potency. To further explore the optimum placement of the acid moiety in conformationally constrained analogs of GW 4064 1a, a series of stilbene replacements were prepared. The benzothiophene 1f and the indole 1g display the optimal orientation of the carboxylate for enhanced FXR agonist potency.