- Modified bile acids: Preparation of 7α,12α-dihydroxy-3β- and 7α,12α-dihydroxy-3α-(2-hydroxyethoxy)-5β-cholanic acid and their biological activity
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Methodology for the preparation of 7α-12α-dihydroxy-3β- (2) and 7α,12α-dihydroxy-3α-(2-hydroxyethoxy)-5β-cholanic acid (3) is described. Nucleophilic displacement of the 3-mesylate of unprotected cholic acid with ethylene glycol led to the 3β-isomer whereas the 3α-isomer was synthesized via the 7,12-diacetyl protected 3-allyl ether of methyl cholate. Only the 3α-isomer 3 is recognized by the ileal bile acid transport system with affinity comparable to cholic acid.
- Wess,Kramer,Bartmann,Enhsen,Glombik,Muellner,Bock,Dries,Kleine,Schmitt
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Read Online
- Leveraging of rifampicin-dosed cynomolgus monkeys to identify bile acid 3-O-sulfate conjugates as potential novel biomarkers for organic anion-transporting polypeptidess
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In the search for novel bile acid (BA) biomarkers of liver organic anion-transporting polypeptides (OATPs), cynomolgus monkeys received oral rifampicin (RIF) at four dose levels (1, 3, 10, and 30 mg/kg) that generated plasma-free Cmax values (0.06, 0.66, 2.57, and 7.79 μM, respectively) spanning the reported in vitro IC50 values for OATP1B1 and OATP1B3 (≤1.7 μM). As expected, the area under the plasma concentration-time curve (AUC) of an OATP probe drug (i.v.2H4-pitavastatin, 0.2 mg/kg) was increased 1.2-, 2.4-, 3.8-, and 4.5-fold, respectively. Plasma of RIF-dosed cynomolgus monkeys was subjected to a liquid chromatography-tandem mass spectrometry method that supported the analysis of 30 different BAs. Monkey urine was profiled, and we also determined that the impact of RIF on BA renal clearance was minimal. Although sulfated BAs comprised only 1% of the plasma BA pool, a robust RIF dose response (maximal ?50-fold increase in plasma AUC) was observed for the sulfates of five BAs [glycodeoxycholate (GDCA-S), glycochenodeoxycholate (GCDCA-S), taurochenodeoxycholate, deoxycholate (DCA-S), and taurodeoxycholate (TDCA-S)]. In vitro, RIF (≤100 μM) did not inhibit cynomolgus monkey liver cytosol-catalyzed BA sulfation and cynomolgus monkey hepatocyte-mediated uptake of representative sulfated BAs (GDCA-S, GCDCA-S, DCA-S, and TDCA-S) was sodium-independent and inhibited (≥70%) by RIF (5 μM); uptake of taurocholic acid was sensitive to sodium removal (74% decrease) and relatively refractory to RIF (≤21% inhibition). We concluded that sulfated BAs may serve as sensitive biomarkers of cynomolgus monkey OATPs and that exploration of their utility as circulating human OATP biomarkers is warranted.
- Thakare, Rhishikesh,Gao, Hongying,Kosa, Rachel E.,Bi, Yi-An,Varma, Manthena V. S.,Cerny, Matthew A.,Sharma, Raman,Kuhn, Max,Huang, Bingshou,Liu, Yiping,Yu, Aijia,Walker, Gregory S.,Niosi, Mark,Tremaine, Larry,Alnouti, Yazen,Rodrigues, A. David
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p. 721 - 733
(2017/06/27)
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- ROR gamma modulators
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The present invention relates to compounds of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention, suppression or amelioration of a disease mediated by the ROR gamma receptor in a subject in need thereof, in particular diabetes and diabetes-related disorders, specifically type II diabetes, methods of their production, as well as methods of treatment or prevention of such diseases.
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Page/Page column 37
(2017/10/25)
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- Novel liver-specific nitric oxide (NO) releasing drugs with bile acid as both NO carrier and targeting ligand
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Novel liver-specific nitric oxide (NO) releasing drugs with bile acid as both the NO carrier and targeting ligand were designed and synthesized by direct nitration of the hydroxyl group in bile acids or the 3-O-hydroxyl alkyl derivatives, with the intact 24-COOH being preserved for hepatocyte specific recognition. Preliminary biological evaluation revealed that oral administrated targeted conjugates could protect mice against acute liver damage induced by acetaminophen or carbon tetrachloride. The nitrate level in the liver significantly increased after oral administration of 1e while nitrate level in the blood did not significantly change. Co-administration of ursodeoxycholic acid (UDCA) significantly antagonized the increase of nitrate in the liver resulted by administration of 1e.
- Jin, Xue-Yuan,Fan, Shi-Yong,Li, Hong-Wu,Shi, Wei-Guo,Chen, Wei,Wang, Hui-Fen,Zhong, Bo-Hua
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p. 787 - 790
(2014/06/09)
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- ROR GAMMA MODULATORS
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The present invention relates to compounds of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention, suppression or amelioration of a disease mediated by the ROR gamma receptor in a subject in need thereof, in particular diabetes and diabetes- related disorders, specifically type II diabetes, methods of their production, as well as methods of treatment or prevention of such diseases.
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Page/Page column 49
(2013/04/10)
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- METHODS FOR PREPARING SYNTHETIC BILE ACIDS AND COMPOSITIONS COMPRISING THE SAME
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This invention relates generally to methods for preparing certain bile acids from non-mammalian sourced starting materials as well as to synthetic bile acids and compositions comprising such acids wherein the acids are characterized by a different C14 population than naturally occurring bile acids as well as being free from any mammalian pathogens. This invention is also directed to the synthesis of intermediates useful in the synthesis of such bile acids. Accordingly, the C ring of the steroidal scaffold is oxidized to provide a synthetic route and intermediates to DCA. This invention also provides synthetic methods for preparing deoxycholic acid or a salt thereof starting from aromatic steroids such as estrogen, equilenin, and derivatives thereof. This invention is also directed to intermediates such as 12-oxo or delta-9,11-ene steroids as well as novel processes for their preparation. In preferred embodiments, bile acids are provided herein which have substituents on the B-ring and/or D-ring side chain and optionally on the hydroxy group of the A-ring.
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- Substituted 4-benzylaminoquinolines and their hetero analogs, process for their preparation, pharmaceuticals containing these compounds and use thereof
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The invention relates to substituted 4-benzylaminoquinolines and their hetero analogs, and to the pharmaceutically acceptable salts and physiologically functional derivatives thereof. Compounds of formula I in which the radicals are defined in the specification, and their physiologically tolerated salts, physiologically functional derivatives and processes for their preparation are described. The compounds are suitable, for example, as medicines for the prophylaxis or treatment of gallstones.
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Page column 13
(2008/06/13)
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- Highly powerful and practical acylation of alcohols with acid anhydride catalyzed by Bi(OTf)3
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Bi(OTf)3-catalyzed acylation of alcohols with acid anhydride was evaluated in comparison with other acylation methods. The Bi(OTf)3/acid anhydride protocol was so powerful that sterically demanding or tertiary alcohols could be acylated smoothly. Less reactive acylation reagents such as benzoic and pivalic anhydride are also activated by this catalysis. In these cases, a new technology was developed in order to overcome difficulty in separation of the acylated product from the remaining acylating reagent: methanolysis of the unreacted anhydride into easily separable methyl ester realized quite easy separation of the desired acylation product. The Bi(OTf)3/acid anhydride protocol was applicable to a wide spectrum of alcohols bearing various functionalities. Acid-labile THP- or TBS-protected alcohol, furfuryl alcohol, and geraniol could be acylated as well as base-labile alcohols. Even acylation of functionalized tertiary alcohols was effected at room temperature.
- Orita,Tanahashi,Kakuda,Otera
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p. 8926 - 8934
(2007/10/03)
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- Cholic acid derivatives as 1,2,4,5-tetraoxane carriers: Structure and antimalarial and antiproliferative activity
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Cholic acid-derived 1,2,4,5-tetraoxanes were synthesized in order to explore the influence of steroid carrier on its antimalarial and antiproliferative activity in vitro. Starting with chiral ketones, cis and trans series of diastereomeric tetraoxanes were obtained, and the cis series was found to be ~2 times as active as the trans against Plasmodium falciparum D6 and W2 clones. The same tendency was observed against human melanoma (Fem-X) and human cervix carcinoma (HeLa) cell lines. The amide C(24) termini, for the first time introduced into the carrier molecule of a tetraoxane pharmacophore, significantly enhanced both antimalarial and antiproliferative activity, as compared to the corresponding methyl esters, with cis-bis(N-propylamide) being most efficient against the chloroquine-susceptible D6 clone (IC50 = 9.29 nM). cis- and trans-bis(N-propylamides) were also screened against PBMC, and PHA-stimulated PBMC, showing a cytotoxicity/antimalarial potency ratio of 1/10 000.
- Opsenica,Pocsfalvi,Juranic,Tinant,Declercq,Kyle,Milhous,Solaja
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p. 3274 - 3282
(2007/10/03)
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- Highly efficient and versatile acylation of alcohols with Bi(OTf)3 as catalyst
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A very convenient route for the acylation of alcohols is provide by using a Bi(OTf)3 catalyst [Eq. (1)]. In this protocol hindered and functionalized alcohols are acylated at 25°C, and solvents can be employed without purification. R= primary, secondary, tertiary alkyl, aryl; R'=Me, Ph, tBu.
- Orita, Akihiro,Tanahashi, Chiaki,Kakuda, Atsushi,Otera, Junzo
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p. 2877 - 2879
(2007/10/03)
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- Cholic Acid as an Architectural Component in Biomimetic/Molecular Recognition Chemistry; Synthesis of the First "Cholaphanes".
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The readily available steroid cholic acid (1) has several advantages as a precursor for extended, preorganised molecular frameworks.In the present work, full details are given for the conversion of 1 into ''cholaphanes'' 2a,b, the first macrocyclic steroi
- Bonar-Law, Richard P.,Davis, Anthony P.
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p. 9829 - 9844
(2007/10/02)
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- Synthesis of Steroidal Cyclodimers from Cholic Acid; a Molecular Framework with Potential for Recognition and Catalysis
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Macrocycles (2a-f) were synthesized from cholic acid (1a) in up to 33 percent overall yield; the 'cholaphane' framework on which they are based has substantial potential variability and should prove useful in biomimetic chemistry.
- Bonar-Law, Richard,Davis, Anthony P.
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p. 1050 - 1052
(2007/10/02)
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