- Exploitation of cholane scaffold for the discovery of potent and selective farnesoid X receptor (FXR) and G-protein coupled bile acid receptor 1 (GP-BAR1) ligands
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Nuclear and G-protein coupled receptors are considered major targets for drug discovery. FXR and GP-BAR1, two bile acid-activated receptors, have gained increasing consideration as druggable receptors. Because endogenous bile acids often target both receptor families, the development of selective ligands has been proven difficult, exposing patients to side effects linked to an unwanted activation of one of the two receptors. In the present study, we describe a novel library of semisynthetic bile acid derivatives obtained by modifications on the cholane scaffold. The pharmacological characterization of this library led to the discovery of 7α-hydroxy-5β-cholan-24-sulfate (7), 6β-ethyl-3α,7β-dihydroxy-5β-cholan-24-ol (EUDCOH, 26), and 6α-ethyl-3α, 7α-dihydroxy-24-nor-5β-cholan-23-ol (NorECDCOH, 30) as novel ligands for FXR and GP-BAR1 that might hold utility in the treatment of FXR and GP-BAR1 mediated disorders.
- Festa, Carmen,Renga, Barbara,D'Amore, Claudio,Sepe, Valentina,Finamore, Claudia,De Marino, Simona,Carino, Adriana,Cipriani, Sabrina,Monti, Maria Chiara,Zampella, Angela,Fiorucci, Stefano
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- Chenodeoxycholic acid derivatives, preparation method thereof and medical application thereof
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The invention relates to the field of medicinal chemistry, relates to chenodeoxycholic acid derivatives, a preparation method thereof and a medical application thereof, in particular to a kind of chenodeoxycholic acid derivatives with a general formula of (I), a preparation method thereof, a pharmaceutical composition comprising the compounds and medical application thereof, especially used as drugs for preventing or treating hyperlipidaemia, type II diabetes, atherosis and non-alcoholic steatohepatitis. The formula is shown in the description.
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- Lipid accumulation inhibitory activities of novel isoxazole-based chenodeoxycholic acids: Design, synthesis and preliminary mechanism study
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In continuation of our drug discovery program on hyperlipidemia, a series of novel isoxazole-chenodeoxycholic acid hybrids were designed, synthesized and evaluated for their lipid-lowering effects. Preliminary screening of all the synthesized compounds was done by using a 3T3-L1 adipocyte model, in which the most active compound 16b could significantly reduce the lipid accumulation up to 30.5% at a nontoxic concentration 10 μM. Further mechanism studies revealed that 16b blocked lipid accumulation via activating FXR-SHP signaling pathway, efficiently down-regulated the expression of key lipogenesis regulator SREBP-1c.
- Qiu, Rongmao,Luo, Guoshun,Li, Xinyu,Zheng, Fan,Li, Haolin,Zhang, Jin,You, Qidong,Xiang, Hua
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p. 2879 - 2884
(2018/07/25)
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- POTENTIAL BILE ACID METABOLITES. X. SYNTHESES OF STEREOISOMERIC 3,7-DIHYDROXY-5α-CHOLANIC ACIDS
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New synthetic routes to allochenodeoxycholic (3α,7α-dihydroxy-5α-cholanic) and alloursodeoxycholic (3α,7β-dihydroxy-5α-cholanic) acids, and their stereoisomers are described.Treatments of allo 7α-hydroxy-3β-tosyloxy ester with N,N-dimethylformamide and of allo 7α-mesyloxy-3β-tosyloxy and 3β-cathyloxy-7α-mesyloxy esters with potassium superoxide-crown ether afforded the desired 3α,7α-, 3α,7β-, and 3β,7β-dihydroxy stereoisomers, respectively, in high yield.Highperformance liquid chromatography was of key importance in characterizing the compounds and determining their purity.Keywords--bile acid; allo bile acid; 3,7-dihydroxy-5α-cholanic acid; allochenodeoxycholic acid; alloursodeoxycholic acid; N,N-dimethylformamide reaction; potassium superoxide-18-crown-6 ether reaction; HPLC
- Iida, Takashi,Momose, Toshiaki,Nambara, Toshio,Chang, Frederic C.
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p. 1929 - 1933
(2007/10/02)
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- Autooxidation of Cholanic Acid in the Presence of Ferrous Ions
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Autooxidation of cholanic acid in an aqueous acetone solution containing 0.2 M acetate buffer (pH 5.0) and ferrous sulfate gave three C(12)-keto products, A, B, and C.The main product A was elucidated to be 12-oxo-5β-cholan-24-oic acid.The minor product B
- Sawaya, Takuji,Kimura, Michiya
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p. 1207 - 1212
(2007/10/02)
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