42017-89-0Relevant articles and documents
Interesting morphological behavior of organic salt choline fenofibrate: Effect of supersaturation and polymeric impurity
Bordawekar, Shailendra,Kuvadia, Zubin,Dandekar, Preshit,Mukherjee, Samrat,Doherty, Michael
, p. 3800 - 3812 (2014)
Crystal habit of drug molecules can have significant influence on the processing and performance of pharmaceutical products. During the development of Trilipix, a pharmaceutical product used for the treatment of mixed dyslipidemia, several crystal habits were observed for the active ingredient choline fenofibrate. The dissolution and performance of the drug product were not impacted by changes in crystal habit of the active ingredient due to high solubility of the drug. However, the formulation process was impacted by variations in crystal habit of the active ingredient, requiring robust control of the crystal habit. The crystal habit was greatly influenced by supersaturation during crystallization from a mixed solvent system comprising methanol and isopropanol. In addition to supersaturation, trace levels of a polymeric impurity in the starting material fenofibrate had a detrimental effect on the crystal habit. This article discusses the effects of these factors on the crystal habit of choline fenofibrate and the design of a crystallization process to deliver the target crystal habit, most suited to the formulation process. The article also provides preliminary mechanistic insights into the crystal habit of this organic salt using an extension of the spiral growth model for morphology prediction of organic molecular crystals. An attempt is made to explain the effect of supersaturation and impurity on the crystal habit of choline fenofibrate using the concepts of stability of surfaces, building units, periodic bond chain theory, and the spiral growth model.
Fenofibric acid
Rath, Nigam P.,Haq, Wahajul,Balendiran, Ganesaratnam K.
, p. o81-o84 (2005)
Unlike the related fenofibrate molecule [Henry, Zhang, Gao & Bruckner (2003). Acta Cryst. E59, o699-o700], fenofibric acid {systematic name: 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic acid}, C17H 15ClO4, contains a carboxylic acid moiety instead of an ester moiety. This polar moiety plays an important role in the formation of a rare acid-to-ketone hydrogen-bond-type packing interaction. The lack of an isopropyl group in fenofibric acid aligns the carboxyl group on the same side as the ketone carbonyl group; this conformation may play an important role in discrimination between the acid and the fenofibrate molecule in molecular recognition.
Targeting lipid metabolism in multiple myeloma cells: Rational development of a synergistic strategy with proteasome inhibitors
Xu, Gaojie,Huang, Sheng,Peng, Jian,Gao, Xiaofang,Li, Minhui,Yu, Sisi,Liu, Zuofeng,Qie, Pengfan,Wang, Yu,Yu, Siqi,Liu, Siyuan,Wen, Hu,Su, Lijuan,Li, Ping,Guang, Bin,Dong, Renhan,Liu, Jin,Yang, Tai
, p. 4741 - 4757 (2021)
Background and Purpose: Aberrant lipid metabolism is recognized as a key feature of cancer cells. Our initial research on MS-based analysis of lipids in a multiple myeloma (MM) cell line showed a significant accumulation of lipids in multiple myeloma cells after proteasome inhibition. This finding prompted us to hypothesize that multiple myeloma cell survival depends on the maximal utilization of abnormally accumulated lipids. Therefore, we explored whether lipid metabolism-modulating agents would synergize with proteasome inhibitors. Experimental Approach: Lipid accumulation in multiple myeloma cells was measured by MS. Synergism between lipid regulators and proteasome inhibitors was assessed by cell viability and apoptosis. A novel stable derivative of fenofibrate (FCE) was synthesized and used to treat multiple myeloma cells in vitro and in vivo along with the proteasome inhibitor ixazomib. ChIP-seq, western blotting and RT-qPCR were performed to explore the potential mechanism(s) underlying the increase in lipid levels in multiple myeloma cells after proteasome inhibition. Key Results: Accumulation of lipids in multiple myeloma cells was induced by proteasome inhibition. Lipid-lowering drugs and MG-132 exerted a synergistic effect to kill multiple myeloma cells. FCE showed significant synergistic activity in vitro and in vivo with ixazomib. The abnormal lipid accumulation in multiple myeloma cells that was enhanced by proteasome inhibitors might be due to the elevated SREBP1/2 expression induced by ATF4. Conclusions and Implications: Our results provide a proof of principle and support for the further clinical evaluation of the combination of lipid-modulating drugs with proteasome inhibitors in the treatment of multiple myeloma.
Influence of lipid lowering fibrates on P-glycoprotein activity in vitro
Ehrhardt, Manuela,Lindenmaier, Heike,Burhenne, Juergen,Haefeli, Walter Emil,Weiss, Johanna
, p. 285 - 292 (2004)
Statin/fibrate combinations are frequently used to treat mixed dyslipidemia. However, these combinations may cause life-threatening drug interactions (e.g. rhabdomyolysis) possibly induced by modifications of cytochrome P450 isozyme activities. Some statins are also transported by P-glycoprotein (Pgp) and may act as inhibitors of this drug efflux pump. So far, nothing is known about possible Pgp modulating effects of fibrates. We tested whether gemfibrozil, fenofibrate, fenofibric acid, and bezafibrate inhibit Pgp in vitro using a calcein acetoxymethylester (calcein-AM) uptake assay and confocal laser scanning microscopy with bodipy-verapamil as substrate in L-MDR1 cells, which overexpress human Pgp. In uptake assays in cells with (L-MDR1) and without (LLC-PK1) human Pgp we also investigated whether these compounds are transported by Pgp. Intracellular concentrations were measured by liquid chromatography tandem mass spectrometry. Of the tested fibrates, only fenofibrate increased calcein-AM uptake into cells indicating an inhibition of Pgp mediated transport by this compound. The potency of fenofibrate (mean±SD: 7.1±3.2μM), evaluated by calculating the concentration needed to double baseline fluorescence (f2), was similar to that of simvastatin (5.8±1.5μM), lovastatin (10.1±1.0), and verapamil (4.7±0.8μM). For simvastatin and fenofibrate Pgp inhibition was confirmed with confocal laser scanning microscopy. Fenofibrate, fenofibric acid, gemfibrozil, and bezafibrate showed no difference in the cellular uptake between LLC-PK1 and L-MDR1, indicating that the tested fibrates are not Pgp substrates. In conclusion, this study demonstrates that fenofibrate inhibits Pgp in vitro with a potency similar to simvastatin.
Cleavage of Carboxylic Esters by Aluminum and Iodine
Sang, Dayong,Yue, Huaxin,Fu, Yang,Tian, Juan
, p. 4254 - 4261 (2021/03/09)
A one-pot procedure for deprotecting carboxylic esters under nonhydrolytic conditions is described. Typical alkyl carboxylates are readily deblocked to the carboxylic acids by the action of aluminum powder and iodine in anhydrous acetonitrile. Cleavage of lactones affords the corresponding ω-iodoalkylcarboxylic acids. Aryl acetylates undergo deacetylation with the participation of the neighboring group. This method enables the selective cleavage of alkyl carboxylic esters in the presence of aryl esters.
Phenoxy acid derivative and application thereof
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Paragraph 0033-0038, (2021/10/05)
The invention relates to a phenoxy acid derivative and application thereof, and specifically provides a compound represented by formula (I-2), or a salt or stereoisomer or deuterated compound thereof. Experiments prove that when the compound represented by the formula (I-2) is combined with a proteasome inhibitor, the growth of tumor cells can be effectively inhibited in vitro, the synergistic anti-tumor activity can be exerted in vivo, and the compound has very good clinical potential in preparation of drugs for treating primary or secondary drug-resistant tumors of the proteasome inhibitor.
Phenoxy aromatic acid with cyclopropyl and pharmaceutically acceptable salt thereof as well as preparation method and application thereof
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Paragraph 0051-0052, (2021/07/17)
The invention provides phenoxy aromatic acid with cyclopropyl, a preparation method of the phenoxy aromatic acid, pharmaceutically acceptable salt of the phenoxy aromatic acid with cyclopropyl and a preparation method of the pharmaceutically acceptable salt, and further provides dosage forms of the phenoxy aromatic acid with cyclopropyl and the pharmaceutically acceptable salt of the phenoxy aromatic acid with cyclopropyl. The invention also discloses application of the compound in medicines for treating hyperlipidemia diseases. The compound provided by the invention has a relatively good blood fat reducing drug effect, so that the compound has a very good application prospect.
Synthesis and evaluation of fenofibric acid ester derivatives: Studies of different formulation with their bioavailability and absorption conditions
Lv, Zhixiang,Wang, Zhou,Xiao, Fuyan,Jin, Guofan
, p. 280 - 287 (2020/01/03)
A series of fenofibric acid ester pro-drugs (JF-1-7) were synthesized. The pharmacokinetic properties of these pro-drugs were examined after oral administration to rats at a dose of 20 mg kg-1 to evaluate the relative bioavailability in rats. The bioavailability of the ester compounds, JF-1, 2, 3, 4, 5, 6, and 7, was significantly higher than that of fenofibrate. In particular, JF-2 proved to be most promising. The oral administration (20 mg kg-1) of JF-2 showed a relative bioavailability of approximately 272.8percent compared to fenofibrate.
Transition-metal-free carbonylation of aryl halides with arylboronic acids by utilizing stoichiometric CHCl3 as the carbon monoxide-precursor
Xu, Fangning,Li, Dan,Han, Wei
supporting information, p. 2911 - 2915 (2019/06/18)
Under transition-metal-free conditions, carbonylative Suzuki couplings of aryl halides with arylboronic acid using stoichiometric CHCl3 as the carbonyl source has been developed. The simple, efficient, and environmentally benign method was successfully applied to the synthesis of Fenofibric acid, naphthyl phenstatin, and carbon-13 labeled biaryl ketone.
Fenofibrate preparation method
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Paragraph 0023; 0026-0028; 0031-0033; 0036-0037, (2019/05/15)
The invention belongs to the technical field of drug preparation, and specifically relates to a fenofibrate preparation method. The preparation method comprises following steps: adding fenofibric acidinto excess isopropanol; then adding a macroporous highly acidic cation exchange resin catalyst, and carrying out esterification reactions at a certain temperature until fenofibric acid is completelyconsumed to obtain fenofibrate; wherein isopropanol is used as a solvent and a reactant. Compared with the prior art, macroporous highly acidic cation exchange resin is taken as a catalyst, has the advantages of large specific surface, high surface activity, high selectivity, few side reactions, and no equipment corrosion, is insoluble to the reaction system, can be easily separated from the reaction system, and can be repeatedly used. The product purification and separation are simplified. The novel catalyst has a wide application prospect.
