Conformationally constrained farnesoid X receptor (FXR) agonists: Heteroaryl replacements of the naphthalene

To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, GSK2324 1c lowered body weight gain and serum glucose in a...

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Veröffentlicht in:	Bioorg. Med. Chem. Lett 2011-02, Vol.21 (4), p.1206-1213
Hauptverfasser:	Bass, Jonathan Y., Caravella, Justin A., Chen, Lihong, Creech, Katrina L., Deaton, David N., Madauss, Kevin P., Marr, Harry B., McFadyen, Robert B., Miller, Aaron B., Mills, Wendy Y., Navas, Frank, Parks, Derek J., Smalley, Terrence L., Spearing, Paul K., Todd, Dan, Williams, Shawn P., Wisely, G. Bruce
Format:	Artikel
Sprache:	eng
Schlagworte:	60 APPLIED LIFE SCIENCES Animals BASIC BIOLOGICAL SCIENCES Bile acid receptor BILE ACIDS Binding Sites Biological and medical sciences Blood Glucose - metabolism Crystallography, X-Ray Diabetes Mellitus, Experimental - metabolism Dogs Farnesoid X receptor Fluorescence Resonance Energy Transfer FXR FXR X-ray co-crystal structure General and cellular metabolism. Vitamins GLUCOSE GSK8062 GW 4064 Humans Isoxazoles - chemical synthesis Isoxazoles - chemistry Isoxazoles - pharmacokinetics Ligands Medical sciences Mice Molecular Conformation NAPHTHALENE Naphthalenes - chemistry NR1H4 GSK2324 Nuclear receptor modulator Pharmacology. Drug treatments Protein Structure, Tertiary QUINOLINES Quinolines - chemical synthesis Quinolines - chemistry Quinolines - pharmacokinetics Rats Receptors, Cytoplasmic and Nuclear - agonists Receptors, Cytoplasmic and Nuclear - metabolism Weight Gain - drug effects
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Zusammenfassung:	To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, GSK2324 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes. To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.12.089