- Discovery of novel ketoxime ether derivatives with potent FXR agonistic activity, oral effectiveness and high liver/blood ratio
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The farnesoid X receptor (FXR) is a promising therapeutic target for nonalcoholic steatohepatitis (NASH) and other bile acid related diseases because it plays a critical role in fibrosis, inflammation and bile acid homeostasis. Obeticholic acid (OCA), a FXR agonist which was synthesized from chenodeoxycholic acid, showed desirable curative effects in clinical trials. However, the pruritus which was the main side effect of OCA limited its further applications in NASH. Although pruritus was also observed in the clinical trials of non-steroidal FXR agonists, the proportion of patients with pruritus was much smaller than that of OCA. Thus, we decided to develop non-steroidal FXR agonists and discovered a series of novel FXR agonists which were synthesized from GW4064 by replacing the stilbene group with ketoxime ether. Encouragingly, in the following biological tests, our target compounds 13j and 13z not only showed potent FXR agonistic activities in vitro, but also effectively promoted the expression of target genes in vivo. More importantly, in the pharmacokinetic experiments, compounds 13j and 13z displayed high liver/blood ratio characteristics which were helpful to reduce the potential side effects which were caused by prolonged systemic activation of FXR. In summary, our compounds were good choices for the development of non-steroidal FXR agonists and were deserved further investigation.
- Tang, Xuehang,Ning, Mengmeng,Ye, Yangliang,Gu, Yipei,Yan, Hongyi,Leng, Ying,Shen, Jianhua
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- PPARs-FXR multi-target micromolecular agonist as well as preparation method and application thereof
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The invention discloses a PPARs-FXR multi-target micromolecule agonist and a preparation method and application thereof, the structure is shown in a general formula I, and the definition of each substituent group is shown in the description and claims. Th
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Paragraph 0092-0096
(2021/05/22)
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- Discovery of BMS-986318, a Potent Nonbile Acid FXR Agonist for the Treatment of Nonalcoholic Steatohepatitis
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Herein we report the discovery and preclinical biological evaluation of 6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)-7-azaspiro[3.5]non-1-en-7-yl)-4-(trifluoromethyl)quinoline-2-carboxylic acid, compound 1 (BMS-986318), a nonbile acid farnesoid X receptor (FXR) agonist. Compound 1 exhibits potent in vitro and in vivo activation of FXR, has a suitable ADME profile, and demonstrates efficacy in the mouse bile duct ligation model of liver cholestasis and fibrosis. The overall profile of compound 1 supports its continued evaluation.
- Azzara, Anthony V.,Cao, Gary G.,Carpenter, Joseph,Cook, Erica M.,Ellsworth, Bruce Alan,Krupinski, Jack,Mosure, Kathy,Rossi, Karen A.,Sitkoff, Doree,Soars, Matthew G.,Wacker, Dean A.,Wang, Tao,Wang, Ying,Wu, Gang,Zhuo, Xiaoliang,Ziegler, Milinda
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p. 1413 - 1420
(2021/08/31)
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- Discovery of a novel and orally active Farnesoid X receptor agonist for the protection of acetaminophen-induced hepatotoxicity
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Acetaminophen (APAP) overdose is a leading cause of acute hepatic failure and liver transplantation, while the existing treatments are poorly effective. Therefore, it is necessary to develop effective therapeutic drugs for APAP-induced hepatotoxicity. Farnesoid X receptor (FXR) is a potential target for the treatment of liver disease, and the activation of FXR protects mice against APAP-induced hepatotoxicity. Compound 5, a glycine-conjugated derivative of FXR agonist 4, was designed to extend the chemical space of existing FXR agonists. Molecular modeling study indicated that compound 5 formed hydrogen bond network with key residues of FXR. Moreover, compound 5 (10?mg/kg) revealed better protective effects against APAP-induced hepatotoxicity than parent compound 4 (30?mg/kg). Further mechanical research indicated that compound 5 regulated the expressions of genes related to FXR and oxidative stress. These findings suggest that compound 5 is a promising FXR agonist suitable for further research, and it is the first time to verify that the glycine-conjugated derivative five exerted better protective effects than its parent compound.
- Cai, Zongyu,Deng, Liming,Hu, Lijun,Li, Zheng,Ren, Qiang,Wang, Bin,Wang, Guangji,Zhao, Xin,Zhou, Zongtao
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- BENZISOXAZOLE COMPOUND
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The present invention provides a compound, a salt thereof, or a prodrug thereof as a compound effective for preventing and/or treating fibrosis, the compound being represented by formula (1) (wherein A is an optionally substituted benzene ring; B is optionally substituted aryl or optionally substituted heteroaryl; X is an oxygen atom or a sulfur atom; Y is a nitrogen atom or a carbon atom; ------ of -----Y is a single or double bond when Y is a carbon atom, or ------ of -----Y is a single bond when Y is a nitrogen atom; each R1 independently represents lower alkyl, or two R1s may be bound to each other to form a spiro ring or a crosslinked structure, or two R1s may be bound to each other to form a saturated fused heterocycle together with nitrogen and carbon atoms constituting a ring containing Y; p is 0, 1, or 2; or (R1)p is oxo) .
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Paragraph 0207-0208; 0222-0223; 0240-0241
(2021/03/13)
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- Dual Farnesoid X Receptor/Soluble Epoxide Hydrolase Modulators Derived from Zafirlukast
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The nuclear farnesoid X receptor (FXR) and the enzyme soluble epoxide hydrolase (sEH) are validated molecular targets to treat metabolic disorders such as non-alcoholic steatohepatitis (NASH). Their simultaneous modulation in vivo has demonstrated a triad of anti-NASH effects and thus may generate synergistic efficacy. Here we report dual FXR activators/sEH inhibitors derived from the anti-asthma drug Zafirlukast. Systematic structural optimization of the scaffold has produced favorable dual potency on FXR and sEH while depleting the original cysteinyl leukotriene receptor antagonism of the lead drug. The resulting polypharmacological activity profile holds promise in the treatment of liver-related metabolic diseases.
- Schierle, Simone,Helmst?dter, Moritz,Schmidt, Jurema,Hartmann, Markus,Horz, Maximiliane,Kaiser, Astrid,Weizel, Lilia,Heitel, Pascal,Proschak, Anna,Hernandez-Olmos, Victor,Proschak, Ewgenij,Merk, Daniel
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- COMPOUNDS USEFUL IN MODULATING THE FARNESOID X RECEPTOR AND METHODS OF MAKING AND USING THE SAME
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Provided are compounds that can act as a modulator of a farnesoid X receptor (FXR) and that can be useful in the treatment of diseases and/or disorders associated with the FXR. Compositions including such compounds are also provided along with methods for preparing compounds of the present invention and their use.
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- Design and Structural Optimization of Dual FXR/PPARδActivators
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Nonalcoholic steatohepatitis (NASH) is considered as severe hepatic manifestation of the metabolic syndrome and has alarming global prevalence. The ligand-activated transcription factors farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) δhave been validated as molecular targets to counter NASH. To achieve robust therapeutic efficacy in this multifactorial pathology, combined peripheral PPAR?-mediated activity and hepatic effects of FXR activation appear as a promising multitarget approach. We have designed a minimal dual FXR/PPARδactivator scaffold by rational fusion of pharmacophores derived from selective agonists. Our dual agonist lead compound exhibited weak agonism on FXR and PPARδand was structurally refined to a potent and balanced FXR/PPARδactivator in a computer-aided fashion. The resulting dual FXR/PPARδmodulator comprises high selectivity over related nuclear receptors and activates the two target transcription factors in native cellular settings.
- Schierle, Simone,Neumann, Sebastian,Heitel, Pascal,Willems, Sabine,Kaiser, Astrid,Pollinger, Julius,Merk, Daniel
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p. 8369 - 8379
(2020/08/12)
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- COMPOUNDS FOR MODULATING FXR
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Provided herein are compounds of Formula (I), a stereoisomer, enantiomer or a pharmaceutically acceptable salt thereof; wherein variables are as defined herein; and their pharmaceutical compositions, which are useful as modulators of the activity of Farnesoid X receptors (FXR).
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- Discovery and Optimization of Non-bile Acid FXR Agonists as Preclinical Candidates for the Treatment of Nonalcoholic Steatohepatitis
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Farnesoid X receptor (FXR) plays a key role in bile acid homeostasis, inflammation, fibrosis, and metabolism of lipid and glucose and becomes a promising therapeutic target for nonalcoholic steatohepatitis (NASH) or other FXR-dependent diseases. The phase III trial results of obeticholic acid demonstrate that the FXR agonists emerge as a promising intervention in patients with NASH and fibrosis, but this bile acid-derived FXR agonist brings severe pruritus and an elevated risk of cardiovascular disease for patients. Herein, we reported our efforts in the discovery of a series of non-bile acid FXR agonists, and 36 compounds were designed and synthesized based on the structure-based drug design and structural optimization strategies. Particularly, compound 42 is a highly potent and selective FXR agonist, along with good pharmacokinetic profiles, high liver distribution, and preferable in vivo efficacy, indicating that it is a potential candidate for the treatment of NASH or other FXR-dependent diseases.
- Li, Junyou,Liu, Mengqi,Li, Yazhou,Sun, Dan-Dan,Shu, Zhihao,Tan, Qian,Guo, Shimeng,Xie, Rongrong,Gao, Lixin,Ru, Hongbo,Zang, Yi,Liu, Hong,Li, Jia,Zhou, Yu
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p. 12748 - 12772
(2020/12/17)
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- Optical control of the nuclear bile acid receptor FXR with a photohormone
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Herein, we report a photoswitchable modulator for a nuclear hormone receptor that exerts its hormonal effects in a light-dependent fashion. The azobenzene AzoGW enables optical control of the farnesoid X receptor (FXR), a key regulator of hepatic bile aci
- Morstein, Johannes,Trads, Julie B.,Hinnah, Konstantin,Willems, Sabine,Barber, David M.,Trauner, Michael,Merk, Daniel,Trauner, Dirk
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p. 429 - 434
(2020/01/21)
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- MULTICYCLIC COMPOUNDS AS FARNESOID X RECEPTOR MODULATORS
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The present invention provides compounds of Formula (I), or stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein all the variables are as defined herein. These compounds modulate the activity of farnesoid X receptor (FXR), for example, as agonists. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating a disease, disorder, or condition associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.
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- SPIROCYCLIC COMPOUNDS AS FARNESOID X RECEPTOR MODULATORS
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The present invention provides compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein all the variables are as defined herein. These compounds modulate the activity of famesoid X receptor (FXR), for example, as agonists. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating a disease, disorder, or condition associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.
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- ALKENE COMPOUNDS AS FARNESOID X RECEPTOR MODULATORS
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The present invention provides compounds of Formula (I): Formula (I) or stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein all the variables are as defined herein. These compounds modulate the activity of famesoid X receptor (FXR), for example, as agonists. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating a disease, disorder, or condition associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.
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- Fluorine-containing isoxazole compound as well as preparation method, pharmaceutical composition and application thereof (by machine translation)
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The invention relates to a fluorine-containing isoxazole compound and a preparation method, a pharmaceutical composition and application thereof. In particular, the present invention discloses a I compound represented by formula (I) or an enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a mixture thereof. And discloses that the compound is a small FXR molecule agonist targeting a molecule, and can be used for treating FXR the disease mediated by the disease. (by machine translation)
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- HORMONE RECEPTOR MODULATORS FOR TREATING METABOLIC CONDITIONS AND DISORDERS
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The invention relates to activators of FXR useful in the treatment of autoimmune disorders, liver disease, intestinal disease, kidney disease, cancer, and other diseases in which FXR plays a role, having the Formula (I): (I), wherein L1, A, X1, X2, R1, R2, and R3 are described herein.
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- A spiro compound, its preparation method, composition and use thereof
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The invention discloses a spiro compound, preparation method thereof, and use of the composition. The spiro compounds have the following formula (I) structure. The invention spiro compounds can be effective therapy [...] X receptor-mediated disease, more stable, long half-life.
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- Novel isoflavone derivative, preparation method therefor and medicinal use of novel isoflavone derivative
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The invention relates to the field of pharmaceutical chemistry, relates to an isoflavone derivative, a preparation method therefor and medicinal use of the novel isoflavone derivative and particularlyrelates to isoflavone derivatives represented by a general formula (I) shown in the description, preparation methods therefor, pharmaceutical compositions containing these compounds and medicinal useof the isoflavone derivatives and the pharmaceutical compositions, particularly use of drugs for preventing or treating hyperlipidemia, type II diabetes, atherosclerosis and non-alcoholic fatty hepatitis.
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- AN ISOXAZOLE DERIVATIVES AS NUCLEAR RECEPTOR AGONISTS AND USED THEREOF
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The present invention relates to isoxazole derivatives, including pharmaceutical compositions and for the preparation of isoxazole derivatives. And more particularly the present invention provided a pharmaceutical composition of isoxazole derivatives for activation of Farnesoid X receptor(FXR, NR1H4).
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- FXR RECEPTOR MODULATOR, PREPARATION METHOD THEREFOR, AND USES THEREOF
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The present disclosure disclosed a modulator of FXR receptor and preparation and use thereof, which relates to the technical filed of medicinal chemistry. The present disclosure provides a modulator of FXR receptor having a structural formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, which can combine with FXR receptor (that is NR1H4) and be acted as a FXR agonist or a partial agonist for preventing and treating the disease mediated by FXR, such as chronic intrahepatic or extrahepatic cholestasis, hepatic fibrosis caused by chronic cholestasis or acute intrahepatic cholestasis, chronic hepatitis B, gallstone, hepatic carcinoma, colon cancer or intestinal inflammatory disease, etc. Specifically, for some chemical compounds, their EC50 for FXR agonist activity reach below 100nM, which show an excellent FXR agonist activity and an excellent prospect to provide a new pharmaceutical selection in clinical treatment for the disease mediated by FXR.
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- A substituted bicyclic compound as bile acid receptors agonist and used thereof
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The present invention relates to a substituted bicyclic compound, a pharmaceutical composition containing the same, and a method for producing the substituted bicyclic compound. In particular, the present invention relates to a pharmaceutical composition for a substituted bicyclic compound for activating a bile acid receptor, fnesr x receptor (fxr, nrlh4).COPYRIGHT KIPO 2018
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- Structure-guided design and synthesis of isoflavone analogs of GW4064 with potent lipid accumulation inhibitory activities
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Our group has previously reported a series of isoflavone derivatives with antidyslipidemic activity. With this background, a series of isoflavone analogs of GW4064 were designed, synthesized and evaluated the lipid-lowering activity of analogs. As a result, most of compounds significantly reduced the lipid accumulation in 3T3-L1 adipocytes and four of them (10a, 11, 15c and 15d) showed stronger inhibitory than GW4064. The most potent compound 15d exhibited promising agonistic activity for FXR in a cell-based luciferase reporter assay. Meanwhile, 15d up-regulated FXR, SHP and BSEP gene expression and down-regulated the mRNA expression of lipogenesis gene SREBP-1c. Besides, an improved safety profile of 15d was also observed in a HepG2 cytotoxicity assay compared with GW4064. The obtained biological results were further confirmed by a molecular docking study showing that 15d fitted well in the binding pocket of FXR and interacted with some key residues simultaneously.
- Qiu, Rongmao,Luo, Guoshun,Cai, Xuerong,Liu, Linyi,Chen, Mingqi,Chen, Deying,You, Qidong,Xiang, Hua
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p. 3726 - 3730
(2018/10/20)
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- ISOXAZOLYL-CARBONYLOXY AZABICYCLO[3.2.1]OCTANYL COMPOUNDS AS FXR ACTIVATORS
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The disclosure relates to activators of FXR useful in the treatment of autoimmune disorders, liver disease, intestinal disease, kidney disease, cancer, and other diseases in which FXR plays a role, having the Formula (I): wherein L1, L2, A, B, R1, R2, R3, and R4 are described herein.
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- ISOXAZOLE DERIVATIVE AS MUTATED ISOCITRATE DEHYDROGENASE 1 INHIBITOR
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It has been found that a compound of the general formula (I) having an isoxazole skeleton has excellent inhibitory activity against mutant IDH1 protein and inhibits the production of 2-HG by this protein, while the compound is also capable of effectively inhibiting the growth of various tumors expressing the protein. In the formula, R1, R2, R3, Y, and Z are as defined in claim 1.
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- Spiro compound and medicinal use thereof
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The invention relates to a spiro compound serving as a FXR receptor agonist, whose chemical structure is shown in type I, pharmaceutically acceptable salts of the spiro compound, or the enantiomers, diastereomers, tautomers, racemates, solvates, N-oxide or amino acid conjugates and the pharmaceutical compositions of the spiro compound, and the use in preparing drugs for treatment of diseases mediated by the FXR receptor.
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- A kind of the second aryl amine derivative and its preparation method, pharmaceutical composition and use thereof
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The invention provides diarylamide type derivatives having a structure shown as a formula (I) as follows, or pharmaceutically acceptable salts thereof, a preparing method of the derivatives, compositions containing the derivatives and the pharmaceutically acceptable salts, and medicine uses of the derivatives and the pharmaceutically acceptable salts. The diarylamide type derivatives having the structure shown as the formula (I) or the pharmaceutically acceptable salts thereof have antagonistic effects on FXR. Integral animal experiments show that the compounds have effects of decreasing blood sugar and reducing blood fat. The compounds can be used for treating hyperlipidemia and type 2 diabetes mellitus.
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- Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH)
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The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonists that introduce a bicyclic nortropine-substituted benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole scaffold. Herein, we report the discovery of 1 (tropifexor, LJN452), a novel and highly potent agonist of FXR. Potent in vivo activity was demonstrated in rodent PD models by measuring the induction of FXR target genes in various tissues. Tropifexor has advanced into phase 2 human clinical trials in patients with NASH and PBC.
- Tully, David C.,Rucker, Paul V.,Chianelli, Donatella,Williams, Jennifer,Vidal, Agnès,Alper, Phil B.,Mutnick, Daniel,Bursulaya, Badry,Schmeits, James,Wu, Xiangdong,Bao, Dingjiu,Zoll, Jocelyn,Kim, Young,Groessl, Todd,McNamara, Peter,Seidel, H. Martin,Molteni, Valentina,Liu, Bo,Phimister, Andrew,Joseph, Sean B.,Laffitte, Bryan
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p. 9960 - 9973
(2018/01/11)
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- Total Facial Discrimination of 1,3-Dipolar Cycloadditions in a d -Erythrose 1,3-Dioxane Template: Computational Studies of a Concerted Mechanism
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A new d-erythrose 1,3-dioxane derivative was synthesized from d-glucose and found to be a highly stereoselective template as a dipolarophile. Different 1,3-dipoles of allenyl-type were employed, giving different regioselectivities, depending on its nature; the regioselectivity is complete with alkyl azides and phenyldiazomethane, but is inexistence with nitrile oxides. Computational studies were performed to understand the mechanisms of cycloadditions. All the studied cycloadditions were found to be concerted involving small free activation energies and are all exoenergonic. The stereoselectivity is due to a combined result of the steric effect H-8a and the hyperconjugative effect of the?C-O to the incoming 1,3-dipole. The regioselectivity observed in alkyl azides and phenyldiazomethane is mostly dependent on the distortion effect during the cycloaddition process. This distortion effect is however higher in the alkyl azide compounds than in phenyldiazomethane.
- Sousa, Cristina E. A.,Ribeiro, António M. P.,Gil Fortes, António,Cerqueira, Nuno M.F.S.A.,Alves, Maria J.
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p. 982 - 991
(2018/06/18)
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- Heterocyclic farnesoid X receptor modifier
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The invention relates to a preparation method of a heterocyclic compound and a composition with components the same as those of the heterocyclic compound and application of the heterocyclic compound as a farnesoid X receptor active modifier. The modifier is the heterocyclic compound shown as the formula I or salt acceptable pharmaceutically or a predrug or a solvent compound or a polycrystal or an isomer or a stable isotope derivative. The compound can be used for treating or preventing related diseases mediated by FXR, and the related diseases are caused by saccharide or lipid or bile metabolic disturbance. The formula I is shown in the specification.
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- Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal Farnesoid X Receptor (FXR) Antagonists: Molecular Basis of FXR Antagonism
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Farnesoid X receptor (FXR) plays an important role in the regulation of cholesterol, lipid, and glucose metabolism. Recently, several studies on the molecular basis of FXR antagonism have been reported. However, none of these studies employs an FXR antagonist with nonsteroidal scaffold. On the basis of our previously reported FXR antagonist with a trisubstituted isoxazole scaffold, a novel nonsteroidal FXR ligand was designed and used as a lead for structural modification. In total, 39 new trisubstituted isoxazole derivatives were designed and synthesized, which led to pharmacological profiles ranging from agonist to antagonist toward FXR. Notably, compound 5s (4′-[(3-{[3-(2-chlorophenyl)-5-(2-thienyl)isoxazol-4-yl]methoxy}-1H-pyrazol-1-yl)methyl]biphenyl-2-carboxylic acid), containing a thienyl-substituted isoxazole ring, displayed the best antagonistic activity against FXR with good cellular potency (IC50=12.2±0.2μM). Eventually, this compound was used as a probe in a molecular dynamics simulation assay. Our results allowed us to propose an essential molecular basis for FXR antagonism, which is consistent with a previously reported antagonistic mechanism; furthermore, E467 on H12 was found to be a hot-spot residue and may be important for the future design of nonsteroidal antagonists of FXR. X marks the spot: 39 trisubstituted isoxazoles were designed and synthesized, leading to compounds with pharmacological profiles ranging from agonist to antagonist at the farnesoid X receptor (FXR). By using the most potent antagonist as a probe, the essential molecular basis of FXR antagonism is proposed, and E467 on H12 can be regarded as a hot-spot residue for the future design of nonsteroidal antagonists of FXR.
- Huang, Huang,Si, Pei,Wang, Lei,Xu, Yong,Xu, Xin,Zhu, Jin,Jiang, Hualiang,Li, Weihua,Chen, Lili,Li, Jian
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p. 1184 - 1199
(2015/07/07)
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- Design, Synthesis, and in Vitro Evaluation of Novel 3, 7-Disubstituted Coumarin Derivatives as Potent Anticancer Agents
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Twenty-seven 3, 7-disubstituted coumarin derivatives were designed, synthesized, and evaluated in vitro as anticancer agents. Most of the compounds showed moderate-to-potent antiproliferative activity against K562 cells. Compounds 7b and 7d were chosen to evaluate the concentration of 50% growth inhibition (GI50) against SN12C, OVCAR, BxPC-3, KATO-III, T24, SNU-1, WiDr, HeLa, K562, and AGS cell lines. The most potent compound 7d was selected for further cell cycle arrest assay in the AGS cell line. The in vitro data indicated that methylation of benzimidazole moiety at the 3-position of coumarin exhibited significant enhancement of anticancer activity. This study should provide important information for further modification and optimization of coumarin derivatives as anticancer agents.
- Wang, Yubin,Liu, Haitao,Lu, Peng,Mao, Rui,Xue, Xiaojian,Fan, Chen,She, Jinxiong
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p. 637 - 647
(2015/03/14)
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- Discovery of 6-(4-{[5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic Acid: A Novel FXR Agonist for the Treatment of Dyslipidemia
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The farnesoid X receptor (FXR) is a member of the "metabolic" subfamily of nuclear receptors. Several FXR agonists have been reported in the literature to have profound effects on plasma lipids in animal models. To discover novel and effective therapies for dyslipidemia and atherosclerosis, we have developed a series of potent FXR agonists that robustly lower plasma LDL and vLDL in LDLr-/- mice. To this end the novel piperidinylisoxazole system LY2562175 was discovered. This molecule is a potent and selective FXR agonist in vitro and has robust lipid modulating properties, lowering LDL and triglycerides while raising HDL in preclinical species. The preclinical ADME properties of LY2562175 were consistent with enabling once daily dosing in humans, and it was ultimately advanced to the clinic for evaluation in humans. The synthesis and biological profile of this molecule is discussed.
- Genin, Michael J.,Bueno, Ana B.,Agejas Francisco, Javier,Manninen, Peter R.,Bocchinfuso, Wayne P.,Montrose-Rafizadeh, Chahrzad,Cannady, Ellen A.,Jones, Timothy M.,Stille, John R.,Raddad, Eyas,Reidy, Charles,Cox, Amy,Michael, M. Dodson,Michael, Laura F.
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p. 9768 - 9772
(2016/01/12)
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- Chemical transformations and photophysical properties of meso-tetrathienyl-substituted porphyrin derivatives
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The chemistry of meso-tetrathienyl-substituted porphyrin derivatives was explored, including synthesis and subsequent metalation, nitration and 1,3-dipolar cycloaddition reactions. Mono- and tetra-nitro-meso- tetrathienylporphyrins were prepared selectively under mild nitration conditions with NaNO2 and trifluoroacetic acid, and the corresponding chlorins and bacteriochlorins were also obtained by reaction with 1,3-dipoles. The products were characterized in detail and their preliminary photophysical properties were evaluated. Copyright
- Betoni Momo, Patricia,Pavani, Christiane,Baptista, Mauricio S.,Brocksom, Timothy John,Thiago De Oliveira, Kleber
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p. 4536 - 4547
(2014/08/05)
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- Design, synthesis and antimycobacterial activity of various 3-(4-(substitutedsulfonyl)piperazin-1-yl)benzo[ d[isoxazole derivatives
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In this communication, we synthesized a series of twenty four novel 3-(4-(substitutedsulfonyl)piperazin-1-yl)benzo[d]isoxazole analogues, characterized using various spectroscopic techniques and evaluated for their in vitro anti-tubercular activity against Mycobacterium tuberculosis (MTB) H37Rv strain. The titled compounds exhibited Minimum inhibitory concentration (MIC) between 3.125 and >50 μg/mL. Among the tested compounds, 5c, 6a, 6j and 6p exhibited moderate activity (MIC Combining double low line 12.5 μg/mL), while 5a and 6i exhibited good activity (MIC Combining double low line 6.25 μg/mL) and 6b (MIC Combining double low line 3.125 μg/mL) exhibited very good anti-tubercular activity. In addition, the analogues 5a, 5c, 6a, 6b, 6i, 6j and 6p were subjected to toxicity studies against mouse macrophage (RAW 264.7) cell lines to analyse the selectivity profile of the newly synthesized compounds and selectivity index of the most active compound was found to be >130 indicating suitability of the compound for further drug development. Structure of 6b was further substantiated through single crystal XRD.
- Naidu, Kalaga Mahalakshmi,Suresh, Amaroju,Subbalakshmi, Jayanty,Sriram, Dharmarajan,Yogeeswari, Perumal,Raghavaiah, Pallepogu,Chandra Sekhar, Kondapalli Venkata Gowri
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- Montmorillonite clay Cu(II) catalyzed domino one-pot multicomponent synthesis of 3,5-disubstituted isoxazoles
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A simple and efficient one-pot multicomponent approach for the synthesis of 3,5-disubstituted isoxazoles directly from corresponding aldehydes and terminal alkynes using recyclable montmorillonite clay supported Cu(II)/NaN3 catalytic system under aqueous conditions have been developed. The 'domino' one-pot MCR approach involves hydroxyamination of aldehydes followed by chlorination and then generation of reactive 'nitrile oxide' which undergoes 1,3-dipolar cycloaddition with alkynes to produce 3,5-disubstituted isoxazoles. The method is operationally simple, regioselective, economical, and possesses excellent functional group compatibility to synthesize structurally diverse isoxazoles in good yields.
- Bharate, Sandip B.,Padala, Anil K.,Dar, Bashir A.,Yadav, Rammohan R.,Singh, Baldev,Vishwakarma, Ram A.
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supporting information
p. 3558 - 3561
(2013/07/05)
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- Synthesis of 1,2,3-triazole substituted isoxazoles via copper (I) catalyzed cycloaddition
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The synthesis of a series of 3,5-disubstituted isoxazole-4-carboxylic esters containing N-substituted 1,2,3-triazoles (V) starting from various benzaldehydes (I) is reported. Benzaldehydes undergo oximation with hydroxylamine hydrosulfate. Later, chlorination followed by condensation with methylacetoacetate and the hydrolysis of the resulting ester afforded respective carboxylic acid (II), which on chlorination with PCl5 gave the corresponding acid chlorides (III). The coraboxylic acid chlorides (III) on propargylation gave propargylic esters (IV) and these on click reaction gave the title compounds (V).
- Ramana, P. Venkata,Reddy, A. Ram
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p. 621 - 627
(2012/09/07)
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- An isomerization-1,3-dipolar cycloaddition tandem reaction towards the synthesis of 3-aryl-4-methyl-5-O-substituted isoxazolines from O-allyl compounds
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A new strategy for the synthesis of 3-aryl-4-methyl-5-O-substituted isoxazolines via tandem catalytic isomerization of O-allyl systems to O-(1-propenyl) systems-1,3-dipolar cycloaddition (1,3-DC) to nitrile oxides is presented. The influence of the heteroatom in Ph-X-CH=CHCH3 (X=O, S, or Se) on the regio- and stereoselectivity of ArCNO 1,3-cycloaddition to these dipolarophiles is analyzed as well. The dipolarophiles were obtained via [RuClH(CO)(PPh3)3]-, [RuH2(CO)(PPh 3)]- or base (KOH/18-crown-6)-catalyzed double bond migration in corresponding allyl ethers, O-allyl acetals, PhS- and PhSe-allyl systems. Cycloadditions of nitrile oxides to O-(1-propenyl) systems were fully regioselective whereas in the reactions of ArCNO with the PhS-(1-propenyl) and PhSe-(1-propenyl) systems both possible regioisomers were formed. It was established that within the majority of dipolarophiles of ROCHCHCH3 type 1,3-DC is concerted, while for some dipolarophiles of RXCH=CHCH3 (X=O and R=Ph3C, 2,3-dihydroxypropyl, tetrahydropyran-2-yl; X=S or Se and R=Ph) type 1,3-DC turns into a two-step reaction with simultaneous rotation about C-C bond. The results of the experiments have been analyzed theoretically using DFT calculations. The results of these calculations agreed well with the experimental data.
- Krompiec, Stanis?aw,Bujak, Piotr,Malarz, Joanna,Krompiec, Micha?,Skórka, ?ukasz,Pluta, Tadeusz,Danikiewicz, Witold,Kania, Magdalena,Kusz, Joachim
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experimental part
p. 6018 - 6031
(2012/09/22)
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- Novel FXR (NR1H4) binding and activity modulating compounds
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The present invention relates to compounds which bind to the NR1H4 receptor (FXR) and act as agonists of the NR1H4 receptor (FXR). The invention further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of said nuclear receptor by said compounds, and to a process for the synthesis of said compounds.
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- NOVEL FXR (NR1H4 ) BINDING AND ACTIVITY MODULATING COMPOUNDS
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The present invention relates to compounds which bind to the NR1 H4 receptor (FXR) and act as agonists of the NR1 H4 receptor (FXR). The invention further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of said nuclear receptor by said compounds, and to a process for the synthesis of said compounds.
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- Synthesis of novel 3, 5-disubstituted-4,5-dihydroisoxazoles and 3,4,5- trisubstituted isoxazoles and their biological activity
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1,3-Dipolar cycloaddition of nitrile oxide generated from substituted pyridinyloxy benzaldoximes with styrene or α,β-unsaturated ketones produces a series of 3,5-disubstituted-4,5-dihydroisoxazoles and 3,4,5-trisubstituted isoxazoles. On the other hand, C
- Shailaja,Manjula,Rao, B. Vittal,Praseeda,Reddy, B. Madhava
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experimental part
p. 214 - 222
(2011/04/16)
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- The first low μM SecA inhibitors
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SecA ATPase is a critical member of the Sec family, which is important in the translocation of membrane and secreted polypeptides/proteins in bacteria. Small molecule inhibitors can be very useful research tools as well as leads for future antimicrobial agent development. Based on previous virtual screening work, we optimized the structures of two hit compounds and obtained SecA ATPase inhibitors with IC50 in the single digit micromolar range. These represent the first low micromolar synthetic inhibitors of bacterial SecA and will be very useful for mechanistic studies.
- Chen, Weixuan,Huang, Ying-ju,Gundala, Sushma Reddy,Yang, Hsiuchin,Li, Minyong,Tai, Phang C.,Wang, Binghe
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scheme or table
p. 1617 - 1625
(2010/05/17)
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- Synthesis of 5-aminoisoxazolines from N-allyl compounds and nitrile oxides via tandem isomerization-1,3-dipolar cycloaddition
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A new strategy for the synthesis of derivatives of 5-aminoisoxazolines via tandem catalytic isomerization (of N-allyl systems to N-(1-propenyl) systems) - 1,3-dipolar cycloaddition (of a stable nitrile oxide to N-(1-propenyl) systems) is presented. Rhodiu
- Bujak, Piotr,Krompiec, Stanis?aw,Malarz, Joanna,Krompiec, Micha?,Filapek, Micha?,Danikiewicz, Witold,Kania, Magdalena,Gbarowska, Katarzyna,Grudzka, Iwona
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experimental part
p. 5972 - 5981
(2010/09/18)
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- COMPOUNDS AND METHODS FOR MODULATING FXR
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Compounds of formula (I): formula (I) wherein variables are as defined herein and their pharmaceutical compositions and methods of use are disclosed as useful for treating dyslipidemia and diseases related to dyslipidemia.
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Page/Page column 55-56; 68-69
(2009/03/07)
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- Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064
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Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.
- Bass, Jonathan Y.,Caldwell, Richard D.,Caravella, Justin A.,Chen, Lihong,Creech, Katrina L.,Deaton, David N.,Madauss, Kevin P.,Marr, Harry B.,McFadyen, Robert B.,Miller, Aaron B.,Parks, Derek J.,Todd, Dan,Williams, Shawn P.,Wisely, G. Bruce
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scheme or table
p. 2969 - 2973
(2010/01/16)
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- Convenient synthesis of isoxazolines via tandem isomerization of allyl compounds to vinylic derivatives and 1,3-dipolar cycloaddition of nitrile oxides to the vinylic compounds
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A novel effective method for the synthesis of new isoxazolines via tandem isomerization of QCH(X)CH{double bond, long}CH(Y) to QC(X){double bond, long}CHCH2(Y) (Q = RO, RS, R2N, R3Si, etc.; X = H, R, OR; Y = H, R; R = alkyl, aryl) catalyzed by ruthenium complexes and 1,3-dipolar cycloaddition of the latter compounds to arenenitrile oxides is presented. The cycloaddition of QCH(X)CH{double bond, long}CH(Y) to 2,6-dichlorobenzonitrile oxide is also described. The regio- and stereoselectivity of the cycloaddition of nitrile oxide to allyl and 1-propenyl (vinylic in general) compounds is discussed.
- Krompiec, Stanis?aw,Bujak, Piotr,Szczepankiewicz, Wojciech
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supporting information; experimental part
p. 6071 - 6074
(2009/04/11)
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- Discovery and optimization of substituted piperidines as potent, selective, CNS-penetrant α4β2 nicotinic acetylcholine receptor potentiators
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The discovery of a series of small molecule α4β2 nAChR potentiators is reported. The structure-activity relationship leads to potent compounds selective against nAChRs including α3β2 and α3β4 and optimized for CNS penetrance. Compounds increased currents through recombinant α4β2 nAChRs, yet did not compete for binding with the orthosteric ligand cytisine. High potency and efficacy on the rat channel combined with good PK properties will allow testing of the α4β2 potentiator mechanism in animal models of disease.
- Albrecht, Brian K.,Berry, Virginia,Boezio, Alessandro A.,Cao, Lei,Clarkin, Kristie,Guo, Wenhong,Harmange, Jean-Christophe,Hierl, Markus,Huang, Liyue,Janosky, Brett,Knop, Johannes,Malmberg, Annika,McDermott, Jeff S.,Nguyen, Hung Q.,Springer, Stephanie K.,Waldon, Daniel,Woodin, Katrina,McDonough, Stefan I.
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scheme or table
p. 5209 - 5212
(2009/05/07)
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- The synthesis of benzhydroximoyl chloride and nitrile oxides under solvent free conditions
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Benzhydroximoyl chlorides were prepared as nitrile oxide precursors with acidic (HCl) silica gel/Oxone in solvent less media in excellent yields with the selective chlorination of aldoximes vs. aromatic substitution. Nitrile oxides were generated by Huisg
- Bigdeli, Mohammad A.,Mahdavinia, Gholam Hossein,Jafari, Saeed
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- HETEROCYCLIC COMPOUNDS HAVING AN OXADIAZOLE MOIETY AND HYDRO ISOMERS THEREOF
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The present invention relates to substituted diphenyl heterocycle compounds having an oxadiazole moiety and pharmaceuticals compositions thereof that inhibit replication of HCV virus. The present invention also relates to the use of the compounds and/or compositions to inhibit HCV replication and/or proliferation and to treat or prevent HCV infections.
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Page/Page column 61
(2008/06/13)
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- HETEROCYCLIC COMPOUNDS AND HYDRO ISOMERS THEREOF
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The present invention relates to substituted diphenyl heterocycle compounds and pharmaceutical compositions thereof that inhibit replication of HCV virus. The present invention also relates to the use of the compounds and/or compositions to inhibit HCV replication and/or proliferation and to treat or prevent HCV infections.
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