Discovery of 3-Aryl-4-isoxazolecarboxamides as TGR5 Receptor Agonists

Evans, Karen A.; Budzik, Brian; Ross, Seamus; Wisnoski, David D.; Jin, Jian; Rivero, Ralph A.; Vimal, Mythily; Szewczyk, George R.; Jayawickreme, Channa; Moncol, David; Rimele, Thomas J.; Armour, Susan; Weaver, Susan P; Griffin, Robert J.; Tadepalli, Sarva M.; Jeune, Michael R.; Shearer, Todd; Chen, Zibin B; Chen, Lihong; Anderson, Donald L.; Becherer, J. David; Frailes, Maite de los; Colilla, Francisco

doi:10.1021/jm901434t

Cited by 67 publications

(60 citation statements)

References 12 publications

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“…In the current study, the GLP-1 response during OGTT was associated with an increase in PYY secretion, another peptide hormone from L-cells (Ballantyne, 2006). Similar responses were seen with specific TGR5 agonists (Evans et al, 2009). During the preparation of this article, Shang et al (2010) reported similar GLP-1 responses during OGTT in diet-induced obesity rats treated with colesevelam.…”

Section: Discussionsupporting

confidence: 74%

Cholestyramine Reverses Hyperglycemia and Enhances Glucose-Stimulated Glucagon-Like Peptide 1 Release in Zucker Diabetic Fatty Rats

Chen

McNulty²,

Anderson³

et al. 2010

J Pharmacol Exp Ther

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Bile acid sequestrants (BAS) have shown antidiabetic effects in both humans and animals but the underlying mechanism is not clear. In the present study, we evaluated cholestyramine in Zucker diabetic fatty (ZDF) rats. Although control ZDF rats had continuous increases in blood glucose and hemoglobin A1c (HbA1c) and serum glucose and a decrease in serum insulin throughout a 5-week study, the cholestyramine-treated ZDF rats showed a dose-dependent decrease and normalization in serum glucose and HbA1c. An oral glucose tolerance test showed a significant increase in glucose-stimulated glucagonlike peptide 1 (GLP-1), peptide YY (PYY), and insulin release in rats treated with cholestyramine. Quantitative analysis of gene expression indicated that cholestyramine treatment decreased farnesoid X receptor (FXR) activity in the liver and the intestine without liver X receptor (LXR) activation in the liver. Moreover, a combination of an FXR agonist with cholestyramine did not reduce the antihyperglycemic effect over cholestyramine alone, suggesting that the FXR-small heterodimer partner-LXR pathway was not required for the glycemic effects of cholestyramine. In summary, our results demonstrated that cholestyramine could completely reverse hyperglycemia in ZDF rats through improvements in insulin sensitivity and pancreatic ␤-cell function. Enhancement in GLP-1 and PYY secretion is an important mechanism for BAS-mediated antidiabetic efficacy.In the last decade, the traditional view of bile acids as essential players in dietary lipid absorption and cholesterol catabolism has changed. The discovery of bile acids as endogenous ligands for the nuclear receptor farnesoid X receptor (FXR; NR1H4) and the G-protein-coupled bile acid receptor (TGR5; GPBAR1) transformed bile acids from lipid absorption facilitator into autocrine, paracrine, and endocrine factors (Parks et al., 1999;Kawamata et al., 2003). In addition to negative feedback regulation of bile acid synthesis in the liver (Makishima et al., 1999), FXR influences many pathways involved in lipid and glucose metabolism (Lefebvre et al., 2009). FXR agonists have been shown to lower circulating cholesterol, triglycerides, and glucose and improve insulin sensitivity in multiple preclinical models (Duran-Sandoval et al., 2005;Stayrook et al., 2005;Cariou et al., 2006;Ma et al., 2006;Zhang et al., 2006). Similar to FXR, TGR5 mediates some hormonal actions of bile acids, including glucose metabolism. It has been demonstrated that bile acids promote glucagon-like-peptide 1 (GLP-1) secretion through TGR5 in STC-1, a murine enteroendocrine cell line (Katsuma et al., Article, publication date, and citation information can be found at

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Section: Discussionsupporting

confidence: 74%

Cholestyramine Reverses Hyperglycemia and Enhances Glucose-Stimulated Glucagon-Like Peptide 1 Release in Zucker Diabetic Fatty Rats

Chen

McNulty²,

Anderson³

et al. 2010

J Pharmacol Exp Ther

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“…The FXR and TGR5 dual agonist 7a, has been shown to improve NAFLD by modulating hepatocyte monocyte activity (McMahan et al, 2013). Other non-bile acid compounds have been reported as specific TGR5 agonists (Evans et al, 2009a;Herbert et al, 2010).…”

Section: Fatty Liver Disease Diabetes and Obesitymentioning

confidence: 99%

Bile Acid Signaling in Metabolic Disease and Drug Therapy

2014

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“…Compound 32, a quinoline, shows modest bioavailability, but increases GLP-1 release and improves oral glucose tolerance in a diet-induced obesity mouse model ( 137 ). A group of isoxazolecarboxamides are potent TGR5 activators, increasing GLP-1 release in dogs while reducing portal vein glucose concentrations ( 138 ). XL475, a third compound, was designed to selectively target TGR5 in the intestine without exerting systemic effects.…”

Section: Fxr Antagonistsmentioning

confidence: 99%