- Nongenomic actions of bile acids. Synthesis and preliminary characterization of 23- and 6,23-alkyl-substituted bile acid derivatives as selective modulators for the G-protein coupled receptor TGR5
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23-Alkyl-substituted and 6,23-alkyl-disubstituted derivatives of chenodeoxycholic acid are identified as potent and selective agonists of TGR5, a G-protein coupled receptor for bile acids (BAs). In particular, we show that methylation at the C-23(S) position of natural BAs confers a marked selectivity for TGR5 over FXR, while the 6α-alkyl substitution increases the potency at both receptors. The present results allow for the first time a pharmacological differentiation of genomic versus nongenomic effects mediated by BA derivatives.
- Pellicciari, Roberto,Sato, Hiroyuki,Gioiello, Antimo,Costantino, Gabriele,Macchiarulo, Antonio,Sadeghpour, Bahman M.,Giorgi, Gianluca,Schoonjans, Kristina,Auwerx, Johan
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- BILE ACID ANALOG TGR5 AGONISTS
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Provided herein are bile acid analogues and derivatives, methods of synthesizing bile acid analogues and derivatives and their use in treating diabetes and liver disease.
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Paragraph 0241; 0204; 0205
(2014/08/06)
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- TGR5 MODULATORS AND METHODS OF USE THEROF
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The invention relates to compounds of Formula A: or a salt, solvate, hydrate, or prodrug thereof. The compounds of Formula A are TGR5 modulators useful for the treatment of various diseases, including metabolic disease, inflammatory disease, liver disease, autoimmune disease, cardiac disease, kidney disease, cancer, and gastrointestinal disease.
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Page/Page column 26
(2010/06/22)
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- TGR5 modulators and methods of use thereof
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The invention relates to compounds of Formula I: or a pharmaceutically effective salt, solvate, hydrate, or prodrug thereof, wherein: R1 is hydrogen, hydroxy, or halogen; R2 is hydrogen or α-hydroxy; R3 is hydroxy, NH(CH2)mSO3H, or NH(CH2)nCO2H; R4 is hydrogen, alkyl, or halogen; R5 is unsubstituted or substituted alkyl, or aryl; R6 is hydrogen or R5 and R6 taken together with the carbons to which they are attached form a ring of size 3, 4, 5, or 6 atoms; m is an integer 0, 1, 2, 3, 4, or 5, and n is an integer 0, 1, 2, 3, 4, or 5. The compounds of Formula I are TGR5 modulators useful for the treatment of various diseases.
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Page/Page column 14
(2008/12/07)
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- Derivatives of biliary acids, process for the production thereof and corresponding pharmaceutical compositions
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New derivatives of chenodeoxycholic, ursodeoxycholic, cholic and ursocholic acids, bearing a methyl group in the side chain, in an alfa position to the carboxylic group, the corresponding nor- and di-nor- derivatives, and the corresponding conjugates with taurine and glycine, are described. The compounds of the invention are prepared by methylation of the esters with methyl iodide in the presence of lithium-dialkylamides.
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