- Synthesis and olfactory activity of unnatural, sulfated 5β-bile acid derivatives in the sea lamprey (Petromyzon marinus)
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A variety of unnatural bile acid derivatives (9a-9f) was synthesized and used to examine the specificity with which the sea lamprey (Petromyzon marinus) olfactory system detects these compounds. These compounds are analogs of petromyzonol sulfate (PS, 1), a component of the sea lamprey migratory pheromone. Both the stereochemical configuration at C5 (i.e., 5α vs. 5β) and the extent and sites of oxygenation (hydroxylation or ketonization) of the bile acid derived steroid skeleton were evaluated by screening the compounds for olfactory activity using electro-olfactogram recording. 5β-Petromyzonol sulfate (9a) elicited a considerable olfactory response at sub-nanomolar concentration. In addition, less oxygenated systems (i.e., 9b-9e) elicited olfactory responses, albeit with less potency. The sea lamprey sex pheromone mimic 9f (5β-3-ketopetromyzonol sulfate) was also examined and found to produce a much lower olfactory response. Mixture studies conducted with 9a and PS (1) suggest that stimulation is occurring via similar modes of activation, demonstrating a relative lack of specificity for recognition of the allo-configuration (i.e., 5α) in sea lamprey olfaction. This attribute could facilitate design of pheromone analogs to control this invasive species.
- Burns, Aaron C.,Sorensen, Peter W.,Hoye, Thomas R.
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- A novel bile acid analog, A17, ameliorated non-alcoholic steatohepatitis in high-fat diet-fed hamsters
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Being endocrine signaling molecules that regulate lipid metabolism and affect energy balance, bile acids are potential drug candidates for non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) could improve NASH accompanied by significant side effects. Therefore, it is worthwhile to develop safer and more effective bile acid analogs. In this study, a new bile acid analog A17 was synthesized and its potential anti-NASH effects were assessed in vitro and in vivo. The impact of A17 on steatosis was investigated in the rat primary hepatocytes challenged with oleic acid. It was found that A17 alleviated lipid accumulation by reducing fatty acid (FA) uptake and promoting FA oxidation. The reduction of FA uptake came from inhibiting fatty acid translocase (Cd36) expression. The promotion of FA oxidation came from stimulating the phosphorylation of adenosine monophosphate (AMP)-activated protein kinase alpha (AMPKα). In addition, A17 reduced lipopolysaccharide-induced inflammation in Raw264.7 cells by activating Takeda G protein-coupled receptor 5 (TGR5). In in vivo study, male Golden Syrian hamsters were fed with high fat (HF) diet and then treated with 50 mg/kg/d A17 for 6 weeks. A17 lowered the lipid profiles and liver enzyme levels in serum and improved liver pathological conditions with less side effects compared with OCA. Further studies confirmed that the molecular mechanisms of A17 in vivo were similar to those in vitro. In conclusion, a novel bile acid analog A17 was identified to ameliorate NASH in HF-fed hamsters. The potential mechanisms could be contributed to reducing FA uptake, stimulating FA oxidation and relieving inflammation.
- Wang, Ying,Zhu, Yao,Niu, Junxing,Deng, Qiangqiang,Guo, Shimeng,Jiang, Haowen,Peng, Zhaoliang,Xue, Yaru,Peng, Huige,Xuan, Lijiang,Pan, Guoyu
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- METHOD FOR PREPARING CHOLIC ACID COMPOUND
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The present application belongs to the field of pharmaceutical chemistry, and relates to a method for preparing a cholic acid compound. Specifically, the present application provides a process for preparing a compound as shown in formula I, comprising subjecting a compound of formula 2 to an oxidization reaction to obtain a compound of formula 3; attaching a trimethylsilyl group to the compound of formula 3 to obtain a compound of formula 4; reacting the compound of formula 4 with acetaldehyde to obtain a compound of formula 5; subjecting the compound of formula 5 to a catalytic hydrogenation reaction to obtain a compound of formula 6; and converting a cyano group of the compound of formula 6 to a carboxyl group to give the compound of formula I. The preparation method has high yield, requires less purification operations, and is suitable for industrial application.
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Paragraph 0069-0070
(2020/12/01)
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- Compound for treating metabolic diseases as well as preparation method and application thereof
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The invention provides a compound for treating metabolic diseases, the compound has a structure represented by formula (I) or formula (II), or a racemate, a stereoisomer, a geometric isomer, a tautomer, a solvate, a hydrate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof. The compounds provided by the invention are FXR and/or TGR5 receptor activators, and the compounds havethe activity of activating FXR and/or TGR5 receptors, and can be used for preparing medicines for treating chronic liver diseases, metabolic diseases or portal hypertension.
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Paragraph 0098-0101
(2019/07/04)
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- COMPOSITIONS AND METHODS FOR TREATING CLOSTRIDIUM ASSOCIATED DISEASES
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The present disclosure provides compounds for preventing, treating, and/or reducing the risk of developing a Clostridium-associated disease in a mammalian subject. Also provided are pharmaceutically acceptable salts of such compounds and compositions that include such compounds and/or pharmaceutically acceptable salts thereof.
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Page/Page column 71
(2017/09/08)
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- Synthesis and Biological Evaluation of Bile Acid Analogues Inhibitory to Clostridium difficile Spore Germination
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Standard antibiotic-based strategies for the treatment of Clostridium difficile infections disrupt indigenous microbiota and commonly fail to eradicate bacterial spores, two key factors that allow recurrence of infection. As an alternative approach to controlling C. difficile infection, a series of bile acid derivatives have been prepared that inhibit taurocholate-induced spore germination. These analogues have been evaluated in a highly virulent NAP1 strain using optical density and phase-contrast microscopy assays. Heterocycle substitutions at C24 were well-tolerated and several tetrazole-containing derivatives were highly potent inhibitors in both assays, with complete inhibition of spore germination observed at 10-25 μM. To limit intestinal absorption, C7-sulfated analogues designed to avoid active and passive transport pathways were prepared. One of these derivatives, compound 21b, was found to be a potent inhibitor of C. difficile spore germination and poorly permeable in a Caco-2 model of intestinal epithelial absorption, suggesting that it is likely to be gut-restricted.
- Stoltz, Kristen L.,Erickson, Raymond,Staley, Christopher,Weingarden, Alexa R.,Romens, Erin,Steer, Clifford J.,Khoruts, Alexander,Sadowsky, Michael J.,Dosa, Peter I.
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p. 3451 - 3471
(2017/05/05)
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- Rational design of nucleoside-bile acid conjugates incorporating a triazole moiety for anticancer evaluation and SAR exploration
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Herein we report a study on the synthesis and biological evaluation of a library of nucleoside-bile acid conjugates prepared by combining 20-deoxyadenosine, 20-deoxyguanosine, 20-deoxyuridine as well as adenosine and guanosine derivatives with cheno-, urso-, nor-cheno-, nor-urso- and taurourso-desoxycholic acid derivatives by means of the click reaction. The new nucleoside-bile acid conjugates incorporating a triazole moiety were tested in vitro against leukemic K562 and HCT116 colon carcinoma, as well as on normal fibroblast cells. Six compounds displayed interesting anti-proliferative activity against the selected cancer lines and no cytotoxic effects against normal fibroblasts. A possible structure activity relationship was also investigated.
- Navacchia, Maria Luisa,Marchesi, Elena,Mari, Lara,Chinaglia, Nicola,Gallerani, Eleonora,Gavioli, Riccardo,Capobianco, Massimo Luigi,Perrone, Daniela
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- CHOLANE DERIVATIVES FOR USE IN THE TREATMENT AND/OR PREVENTION OF FXR AND TGR5/GPBAR1 MEDIATED DISEASES
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13073PTWO 56 ABSTRACT The present invention relates to compounds having cholane scaffolds of formula (I), said compounds for use in the treatment and/or prevention of FXR and TGR5/GPBAR1 mediated diseases. 5
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Page/Page column 20
(2015/12/17)
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- Modification on ursodeoxycholic acid (UDCA) scaffold. Discovery of bile acid derivatives as selective agonists of cell-surface G-protein coupled bile acid receptor 1 (GP-BAR1)
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Bile acids are signaling molecules interacting with the nuclear receptor FXR and the G-protein coupled receptor 1 (GP-BAR1/TGR5). GP-BAR1 is a promising pharmacological target for the treatment of steatohepatitis, type 2 diabetes, and obesity. Endogenous bile acids and currently available semisynthetic bile acids are poorly selective toward GP-BAR1 and FXR. Thus, in the present study we have investigated around the structure of UDCA, a clinically used bile acid devoid of FXR agonist activity, to develop a large family of side chain modified 3,7 dihydroxyl cholanoids that selectively activate GP-BAR1. In vivo and in vitro pharmacological evaluation demonstrated that administration of compound 16 selectively increases the expression of pro-glucagon 1, a GP-BAR1 target, in the small intestine, while it had no effect on FXR target genes in the liver. Further, compound 16 results in a significant reshaping of bile acid pool in a rodent model of cholestasis. These data demonstrate that UDCA is a useful scaffold to generate novel and selective steroidal ligands for GP-BAR1.
- Sepe, Valentina,Renga, Barbara,Festa, Carmen,Damore, Claudio,Masullo, Dario,Cipriani, Sabrina,Di Leva, Francesco Saverio,Monti, Maria Chiara,Novellino, Ettore,Limongelli, Vittorio,Zampella, Angela,Fiorucci, Stefano
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p. 7687 - 7701
(2014/12/12)
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- Optimized synthesis of pure, non-polymorphic, crystalline bile acids with defined particle size
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The present invention relates to a pure polymorph of Nor-UDCA or Bis-nor-UDCA, or of a pharmaceutically acceptable salt thereof. The invention further provides a pharmaceutical composition comprising the polymorph of the invention, and a method for preparing the polymorph. The invention includes the pharmaceutical use of the polymorph or of the pharmaceutical composition of the invention.
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Page/Page column 6
(2012/07/03)
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- Synthesis, characterization and biological activity of hydroxyl- bisphosphonic analogs of bile acids
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Bisphosphonates (BPs) are now the most widely used drugs for diseases associated with increased bone resorption, such as osteoporosis, and tumor bone diseases. A significant drawback of the BPs is their poor oral absorption that is enhanced by the presence of bile acid substituents in the bisphosphonate framework, with no toxic effects. A straightforward synthesis of bile acid-containing hydroxy-bisphosphonates and a full characterization of these pharmaceutically important molecules, including an evaluation of affinity and the mechanism of binding to hydroxyapatite, is presented. The biological activity of bile acid-containing bisphosphonate salts was determined using the neutral-red assay on the L929 cell line and primary cultures of osteoclasts. The bioactivity of the new compounds was found superior than bisphosphonates of established activity.
- Bortolini, Olga,Fantin, Giancarlo,Fogagnolo, Marco,Rossetti, Stefano,Maiuolo, Loredana,Di Pompo, Gemma,Avnet, Sofia,Granchi, Donatella
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body text
p. 221 - 229
(2012/07/28)
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- OPTIMIZED SYNTHESIS OF PURE, NON-POLYMORPHIC, CRYSTALLINE BILE ACIDS WITH DEFINED PARTICLE SIZE
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The present invention relates to a pure polymorph of Nor-UDCA or Bis-nor-UDCA, or of a pharmaceutically acceptable salt thereof. The invention further provides a pharmaceutical composition comprising the polymorph of the invention, and a method for preparing the polymorph. The invention includes the pharmaceutical use of the polymorph or of the pharmaceutical composition of the invention.
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Page/Page column 13
(2012/06/16)
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- Ursodeoxycholic acid amides as novel glucocorticoid receptor modulators
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Ursodeoxycholic acid (UDCA) is used for the treatment of hepatic inflammatory diseases. Recent studies have shown that UDCAs biological effects are partly glucocorticoid receptor (GR) mediated. UDCA derivatives were synthesized and screened for ability to
- Sharma, Ruchika,Prichard, David,Majer, Ferenc,Byrne, Anne-Marie,Kelleher, Dermot,Long, Aideen,Gilmer, John F.
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scheme or table
p. 122 - 130
(2011/03/19)
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- BILE ACID DERIVATIVES AS FXR LIGANDS FOR THE PREVENTION OR TREATMENT OF FXR-MEDIATED DISEASES OR CONDITIONS
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The present invention relates to compounds of formula (I) wherein: R1 is hydrogen or an alkyl group; R2 is hydrogen or a halogen, nitro, alkyloxy, amino or carboxy group; Y is CH2, oxygen or sulfur; n is an integer from 1
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(2010/04/23)
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- Synthesis and in vitro cholesterol dissolution by 23- and 24-phosphonobile acids
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A new class of 23- and 24-phosphonobile acids have been synthesized from bile acid and their in vitro cholesterol-dissolving efficiency have been estimated. 24-Phosphonobile salts (PBSs) are slightly more efficient in solubilizing cholesterol than 23-PBSs and natural bile salts. The cholesterol solubilizing power is influenced by the structure of PBSs, and is considerably reduced with an increase in the bulk pH.
- Babu, Ponnusamy,Maitra, Uday
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p. 681 - 689
(2007/10/03)
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- Anti-fungal compounds
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Compounds of the general formula (7): STR1 wherein X is a hydrogen atom or a hydroxyl group, Y is a hydrogen atom or a hydroxyl group and at least one of X and Y is a hydroxyl group and Z is a hydroxyl group or a methylol (--CH2 OH) group, have anti-fungal activity, especially against organisms selected from Candida spp. and the athlete's foot/ringworm organisms Trichophyton mentagrophytes and Microsporum audonii. Compounds in which Z is a methylol (--CH2 OH) group are claimed per se.
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- Synthesis of homoursodeoxycholic acid and 3H>homoursodeoxycholic acid
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Homoursodeoxycholic acid and 3H>homoursodeoxycholic acid were synthesized from ursodeoxycholic acid and homocholic acid, respectively.Ursodeoxycholic acid (Ia) was converted to 3α,7β-diformoxy-5β-cholan-24-oic acid (Ib) using formic acid.Reaction of the diformoxy derivative (Ib) with thionyl chloride yielded the acid chloride (II) which was treated with diazomethane to produce 3α,7β-diformoxy-25-diazo-25-homo-5β-cholan-24-one (III).Homoursodeoxycholic acid (IV) was formed from the diazoketone (III) by means of the Wolff rearrangement of the Arndt-Eistert synthesis.N-Bromosuccinimide oxidation of homocholic acid (V), which was prepared from cholic acid by the same procedure described above, afforded 3α,12α-dihydroxy-7-oxo-25-homo-5β-cholan-25-oic acid (VI).Reduction of the 7-ketohomodeoxycholic acid (VI) with sodium in 1-propanol gave 3α,7β,12α-trihydroxy-25-homo-5β-cholan-25-oic acid (VII).The methyl ester of 7-epihomocholic acid (VII) was partially acetylated to give methyl 3α,7β-diacetoxy-12α-hydroxy-25-homo-5β-cholan-25-oate (VIII) using a mixture of acetic anhydride, pyridine and benzene.Dehydration of the diacetoxy derivative (VIII) with phosphorus oxychloride yielded methyl 3α,7β-diacetoxy-25-homo-5β-chol-11-en-25-oate (IX).Reduction of the unsaturated ester (IX) with tritium gas in the presence of platinum oxide catalyst followed by alkaline hydrolysis gave 3H>homoursodeoxycholic acid.
- Kuramoto, Taiju,Kawamoto, Keiki,Moriwaki, Shigeru,Hoshita, Takahiko
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p. 549 - 559
(2007/10/02)
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- The preparation of bile acid amines and oxazolines. II. The synthesis of the amides and oxazolines of ursodeoxycholic acid, deoxycholic acid, hyodeoxycholic acid and cholic acid
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Bile acid amides and oxazolines were synthesized by a sequence of steps involving the reaction of the free bile acid with formic acid to yield the formyloxy derivative, preparation of the formyloxy acid chloride, condensation of the acid chloride with 2-amino-2-methyl-1-propanol to give the amide and, finally, cyclization of the amide with thionyl chloride to give the oxazoline. The oxazolines were characterized by physical constants, thin layer and gas-liquid chromatography and identified by elemental analysis and gas-liquid chromatography-mass spectrometry. Some of the bile acid oxazoline derivatives alter the activity of bacterial 7-dehydroxylases in vitro, and inhibit the growth of certain anaerobic bacteria in pure culture.
- Cohen,May,McSherry,Mosbach
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p. 701 - 711
(2007/10/02)
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- THE PREPARATION OF BILE ACID AMIDES AND OXAZOLINES
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Amides obtained by the condensation of some bile acid chlorides with 2-amino-2-methyl-1-propanol on cyclization yield bile acid oxazolines.Physical properties of these bile acid derivatives are described.Some of the oxazolines are non-toxic and are inhibitors of 7-dehydroxylaseactivity in fecal anaerobic bacteria and purified enzymes from these bacteria.
- Ayengar, Narayan K. N.,Singhal, Anil K.,McSherry Charles K.,Mosbach, Erwin H.
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p. 333 - 346
(2007/10/02)
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- New bile alcohols - synthesis of 5β cholestane 3α,7α, 3α,7α,25 and 5β cholestane 3α,7α,25-24(14C) triol
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5β Cholestane 3α,7α,25 triol and 5β cholestane 3α,7α,24-25(14C) triol were synthesized from 3α,7α dihydroxy 5β cholanoic acid (chenodeoxycholic acid). Chenodeoxycholic acid was converted to the diformoxy derivative (II) using formic acid. Reaction of II with thionyl chloride yielded the acid chloride which was treated with diazomethane (CH2N2 or 14CH2N2) to produce 3α,7α diformoxy 24 oxo 25 diazo 25 homocholane (III, A or B). 25 Homochenodeoxycholic acid (IV A or B) was formed from III by means of the Wolff rearrangement of the Arndt Eistert synthesis. The methyl ester of V (A or B) was treated with methyl magnesium iodide in ether to provide the desired triol, VI (A and B). The triol was identified by mass spectrometry and elemental analysis and was characterized by thin layer and gas liquid chromatography. The 3α,7α,25 triol is of possible significance as an intermediate in the pathway of bile acid formation from cholesterol.
- Cohen,Tint,Kuramoto,Mosbach
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p. 365 - 378
(2007/10/17)
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