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, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.

[1]  G. Kullak-Ublick,et al.  The role of FXR in disorders of bile acid homeostasis. , 2008, Physiology.

[2]  A. Morelli,et al.  A Farnesoid X Receptor-Small Heterodimer Partner Regulatory Cascade Modulates Tissue Metalloproteinase Inhibitor-1 and Matrix Metalloprotease Expression in Hepatic Stellate Cells and Promotes Resolution of Liver Fibrosis , 2005, Journal of Pharmacology and Experimental Therapeutics.

[3]  A. Morelli,et al.  Cross-Talk between Farnesoid-X-Receptor (FXR) and Peroxisome Proliferator-Activated Receptor γ Contributes to the Antifibrotic Activity of FXR Ligands in Rodent Models of Liver Cirrhosis , 2005, Journal of Pharmacology and Experimental Therapeutics.

[4]  S. Kliewer,et al.  FXR agonists and FGF15 reduce fecal bile acid excretion in a mouse model of bile acid malabsorption Published, JLR Papers in Press, September 6, 2007. , 2007, Journal of Lipid Research.

[5]  D. Moore,et al.  Nuclear Receptor-Dependent Bile Acid Signaling Is Required for Normal Liver Regeneration , 2006, Science.

[6]  A. Grefhorst,et al.  Transient impairment of the adaptive response to fasting in FXR‐deficient mice , 2005, FEBS letters.

[7]  R. Evans,et al.  Benefit of farnesoid X receptor inhibition in obstructive cholestasis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Sander M Houten,et al.  Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. , 2004, The Journal of clinical investigation.

[9]  M. Bowman,et al.  A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. , 2003, Molecular cell.

[10]  Songwen Zhang,et al.  Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. , 2009, Journal of hepatology.

[11]  M. Evans,et al.  Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR−/− and apoE−/− mice Published, JLR Papers in Press, January 27, 2009. , 2009, Journal of Lipid Research.

[12]  U. Deuschle,et al.  Synthesis and pharmacological validation of a novel series of non-steroidal FXR agonists. , 2010, Bioorganic & medicinal chemistry letters.

[13]  A. Morelli,et al.  The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. , 2004, Gastroenterology.

[14]  J. Tolan,et al.  MDCK (Madin-Darby canine kidney) cells: A tool for membrane permeability screening. , 1999, Journal of pharmaceutical sciences.

[15]  S. Kliewer,et al.  Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. , 2005, Cell metabolism.

[16]  J. Ward,et al.  Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. , 2007, Carcinogenesis.

[17]  T. Willson,et al.  Protective Effects of 6-Ethyl Chenodeoxycholic Acid, a Farnesoid X Receptor Ligand, in Estrogen-Induced Cholestasis , 2005, Journal of Pharmacology and Experimental Therapeutics.

[18]  Shawn P Williams,et al.  Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064. , 2008, Bioorganic & medicinal chemistry letters.

[19]  B. Staels,et al.  FXR: a promising target for the metabolic syndrome? , 2007, Trends in pharmacological sciences.

[20]  Timothy M Willson,et al.  Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[21]  C. J. Sinal,et al.  Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice Published, JLR Papers in Press, September 26, 2005. DOI 10.1194/jlr.M500390-JLR200 , 2005, Journal of Lipid Research.

[22]  Hans Richter,et al.  Identification of an N-oxide pyridine GW4064 analog as a potent FXR agonist. , 2009, Bioorganic & medicinal chemistry letters.

[23]  P. Dent,et al.  Bile acids as regulatory molecules , 2009, Journal of Lipid Research.

[24]  Shawn P Williams,et al.  Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064. , 2009, Bioorganic & medicinal chemistry letters.

[25]  L. Moore,et al.  Identification of a chemical tool for the orphan nuclear receptor FXR. , 2000, Journal of medicinal chemistry.

[26]  Grace Guo,et al.  The Farnesoid X-receptor Is an Essential Regulator of Cholesterol Homeostasis* , 2003, The Journal of Biological Chemistry.

[27]  T. Willson,et al.  6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. , 2002, Journal of medicinal chemistry.

[28]  Ke Ma,et al.  Farnesoid X receptor is essential for normal glucose homeostasis. , 2006, The Journal of clinical investigation.

[29]  R. Evans,et al.  A nuclear receptor-mediated xenobiotic response and its implication in drug metabolism and host protection. , 2003, Current drug metabolism.

[30]  Shawn P. Williams,et al.  FXR agonist activity of conformationally constrained analogs of GW 4064. , 2009, Bioorganic & medicinal chemistry letters.

[31]  Yun Yen,et al.  Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. , 2007, Cancer research.

[32]  B. Cariou.  The farnesoid X receptor (FXR) as a new target in non-alcoholic steatohepatitis. , 2008, Diabetes & metabolism.

[33]  Jasmine Chen,et al.  Identification of a nuclear receptor that is activated by farnesol metabolites , 1995, Cell.

[34]  S. Asano,et al.  Immunolocalization of farnesoid X receptor (FXR) in mouse tissues using tissue microarray. , 2008, Acta histochemica.

[35]  P. Edwards,et al.  FXR Deficiency Causes Reduced Atherosclerosis in Ldlr−/− Mice , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[36]  Masataka Harada,et al.  A G Protein-coupled Receptor Responsive to Bile Acids* , 2003, The Journal of Biological Chemistry.

[37]  A. Bookout,et al.  Prevention of cholesterol gallstone disease by FXR agonists in a mouse model , 2004, Nature Medicine.

[38]  B. Staels,et al.  Role of bile acids and bile acid receptors in metabolic regulation. , 2009, Physiological reviews.

[39]  Stefan Westin,et al.  Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR). , 2009, Journal of medicinal chemistry.

[40]  Bryan Goodwin,et al.  Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. , 2003, The Journal of clinical investigation.

[41]  S. Kliewer,et al.  Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[42]  P. Dent,et al.  Down-regulation of Cholesterol 7α-Hydroxylase (CYP7A1) Gene Expression by Bile Acids in Primary Rat Hepatocytes Is Mediated by the c-Jun N-terminal Kinase Pathway* , 2001, The Journal of Biological Chemistry.