865244-30-0Relevant articles and documents
3β-Isoobeticholic acid efficiently activates the farnesoid X receptor (FXR) due to its epimerization to 3α-epimer by hepatic metabolism
Drastik, Martin,Holas, Ondrej,Hroch, Milos,Kaspar, Miroslav,Kudova, Eva,Micuda, Stanislav,Pandey, Amit V.,Pavek, Petr,Skoda, Josef,Smutny, Tomas,Stefela, Alzbeta,Hutníková, Miriama
, (2020)
Bile acids (BAs) are important signaling molecules acting via the farnesoid X nuclear receptor (FXR) and the membrane G protein-coupled bile acid receptor 1 (GPBAR1). Besides deconjugation of BAs, the oxidoreductive enzymes of colonic bacteria and hepatocytes enable the conversion of BAs into their epimers or dehydrogenated forms. Obeticholic acid (OCA) is the first-in-class BA-derived FXR agonist approved for the treatment of primary biliary cholangitis. Herein, a library of OCA derivatives, including 7-keto, 6-ethylidene derivatives and 3β-epimers, was synthetized and investigated in terms of interactions with FXR and GPBAR1 in transaction assays and evaluated for FXR target genes expression in human hepatocytes and C57BL/6 mice. The derivatives were further subjected to cell-free analysis employing in silico molecular docking and a TR-FRET assay. The conversion of the 3βhydroxy epimer and its pharmacokinetics in mice were studied using LC–MS. We found that only the 3β-hydroxy epimer of OCA (3β-isoOCA) possesses significant activity to FXR in hepatic cells and mice. However, in a cell-free assay, 3β-isoOCA had about 9-times lower affinity to FXR than did OCA. We observed that 3β-isoOCA readily epimerizes to OCA in hepatocytes and murine liver. This conversion was significantly inhibited by the hydroxy-Δ5-steroid dehydrogenase inhibitor trilostane. In addition, we found that 3,7-dehydroobeticholic acid is a potent GPBAR1 agonist. We conclude that 3β-isoOCA significantly activates FXR due to its epimerization to the more active OCA by hepatic metabolism. Other modifications as well as epimerization on the C3/C7 positions and the introduction of 6-ethylidene in the CDCA scaffold abrogate FXR agonism and alleviate GPBAR1 activation.
A process for preparing [...] method (by machine translation)
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Paragraph 0097; 0107-0113, (2018/07/30)
The invention discloses a method for preparing [...] intermediate and [...] method, intermediate synthetic route is: Preparation method of the invention, in the course of reacting with good stereoselectivity, greatly simplifying the [...] synthetic difficulty, reduces the cost of synthesizing of [...]. The mild reaction conditions of the present invention, industrially easy to realize, can get low impurity of the midbody and [...][...]. The raw material used by the security, the cost is low, effectively reduces the production cost. (by machine translation)
STEROID 6.7Β-EPOXIDES AS CHEMICAL INTERMEDIATES
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, (2017/12/18)
The invention relates to a process for preparing a compound of general formula (Ia): wherein R2, Y, R4 and R5 are as defined herein. The invention also relates to certain compounds perse. The compounds are intermediates in the synthesis of synthetic bile acids.
BILE ACID DERIVATIVES AND METHODS FOR SYNTHESIS AND USE
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Paragraph 0415-0417, (2017/12/27)
Provided herein, inter alia, are methods for the preparation of modulators of farnesoid X receptor (FXR), and compositions and uses of the modulators of FXR.
Novel FXR (farnesoid X receptor) modulators: Potential therapies for cholesterol gallstone disease
Yu, Donna D.,Andrali, Sreenath S.,Li, Hongzhi,Lin, Min,Huang, Wendong,Forman, Barry M.
, p. 3986 - 3993 (2016/08/23)
Metabolic disorders such as diabetes are known risk factors for developing cholesterol gallstone disease (CGD). Cholesterol gallstone disease is one of the most prevalent digestive diseases, leading to considerable financial and social burden worldwide. Ursodeoxycholic acid (UDCA) is the only bile acid drug approved by FDA for the non-surgical treatment of gallstones. However, the molecular link between UDCA and CGD is unclear. Previous data suggest that the farnesoid X receptor (FXR), a bile acid nuclear receptor, may protect against the development of CGD. In studies aimed at identifying the role of FXR, we recently identify a novel chemical tool, 6EUDCA (6-αethyl-ursodeoxycholic acid), a synthetic derivative of UDCA, for studying FXR. We found that 6EUDCA binds FXR stronger than UDCA in a TR-FRET binding assay. This result was supported by computational docking models that suggest 6EUDCA forms a more extensive hydrogen bound network with FXR. Interestingly, neither compound could activate FXR target genes in human nor mouse liver cells, suggesting UDCA and 6EUDCA activate non-genomic signals in an FXR-dependent manner. Overall these studies may lead to the identification of a novel mechanism by which bile acids regulate cell function, and 6EUDCA may be an effective targeted CGD therapeutic.
Method for synthesizing, separating and determining obeticholic acid (OCA) isomer
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, (2016/10/08)
The invention relates to an obeticholic acid (OCA) isomer namely an OCA-alpha alpha beta body, a synthetic method of the OCA-alpha beta alpha body, and a method adopting the reversed phase liquid chromatography condition to separate the OCA isomer. With adoption of the technical scheme disclosed by the invention, the OCA-alpha alpha beta body and the OCA-alpha beta alpha body with the HPLC purity greater than 98% can be obtained to meet quality control of the isomer in OCA.
BILE ACID ANALOG TGR5 AGONISTS
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, (2014/08/06)
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.
Novel steroid agonist for FXR
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Page/Page column 8-9, (2008/06/13)
The invention relates to a FXR agonist of formula (I): ???and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof.
