- Interesting morphological behavior of organic salt choline fenofibrate: Effect of supersaturation and polymeric impurity
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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.
- Bordawekar, Shailendra,Kuvadia, Zubin,Dandekar, Preshit,Mukherjee, Samrat,Doherty, Michael
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- Fenofibric acid
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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.
- Rath, Nigam P.,Haq, Wahajul,Balendiran, Ganesaratnam K.
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- Targeting lipid metabolism in multiple myeloma cells: Rational development of a synergistic strategy with proteasome inhibitors
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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.
- 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
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- Influence of lipid lowering fibrates on P-glycoprotein activity in vitro
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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.
- Ehrhardt, Manuela,Lindenmaier, Heike,Burhenne, Juergen,Haefeli, Walter Emil,Weiss, Johanna
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- Cleavage of Carboxylic Esters by Aluminum and Iodine
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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.
- Sang, Dayong,Yue, Huaxin,Fu, Yang,Tian, Juan
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p. 4254 - 4261
(2021/03/09)
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- Phenoxy acid derivative and application thereof
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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.
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Paragraph 0033-0038
(2021/10/05)
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- Phenoxy aromatic acid with cyclopropyl and pharmaceutically acceptable salt thereof as well as preparation method and application thereof
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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.
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Paragraph 0051-0052
(2021/07/17)
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- Synthesis and evaluation of fenofibric acid ester derivatives: Studies of different formulation with their bioavailability and absorption conditions
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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.
- Lv, Zhixiang,Wang, Zhou,Xiao, Fuyan,Jin, Guofan
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p. 280 - 287
(2020/01/03)
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- Fenofibrate preparation method
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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.
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Paragraph 0023; 0026-0028; 0031-0033; 0036-0037
(2019/05/15)
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- Transition-metal-free carbonylation of aryl halides with arylboronic acids by utilizing stoichiometric CHCl3 as the carbon monoxide-precursor
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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.
- Xu, Fangning,Li, Dan,Han, Wei
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supporting information
p. 2911 - 2915
(2019/06/18)
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- Synthesis technology of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl propionic acid
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The invention relates to a synthesis technology of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl propionic acid. The invention aims to solve the technical problems that a conventional fenofibric acid synthesis method has violent reaction in the preparation process and the purity of prepared products is low. The technical scheme comprises that the synthesis technology of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl propionic acid includes the steps: under an alkaline condition, carrying out a substitution reaction of (4-chloro-phenyl)-(4-hydroxy-phenyl)-methanone with 2-ethyl bromoisobutyrate in an organic solvent to obtain 2-[4-(4-chloro-benzoyl)-phenoxy]-2-methyl-ethyl propionate; hydrolyzing the obtained product in an organic solvent under an alkaline condition, to obtain a 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl propionic acid crude product; and carrying out recrystallization of the compound crude product obtained from hydrolysis for two times to obtain the target product.
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Paragraph 0024-0027; 0031-0035; 0037-0039; 0043-0045
(2018/03/07)
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- New photosafety assessment strategy based on the photochemical and pharmacokinetic properties of both parent chemicals and metabolites
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Photoreactivity and dermal/ocular deposition of compounds have been recognized as key considerations for evaluating the phototoxic risk of compounds. Because some drugs are known to cause phototoxic reactions via generation of potent phototoxic metabolites, photosafety assessments on parent drugs alone may lead to false predictions about their photosafety. This study aimed to establish a new photosafety assessment strategy for evaluating the in vivo phototoxic potential of both a parent substance and its metabolites. The in vivo phototoxic risk of fenofibrate (FF) and its metabolites, fenofibric acid (FA) and reduced fenofibric acid, were evaluated based on photochemical and pharmacokinetic analyses. FF and FA exhibited intensive UV absorption, with molar extinction coefficient values of 17,000 (290nm) and 14,000 M-1cm-1 (295 nm), respectively. Superoxide generation from FA was significantly higher than from FF, and a marked increase in superoxide generation from FF was observed after incubation with rat hepatic S9 fractions, suggesting enhanced photoreactivity of FF after metabolism. FA showed high dermal/ocular deposition after oral administration (5 mg/kg, p.o.) although the concentration of FF was negligible, suggesting high exposure risk from FA. On the basis of these findings, FA was deduced to be a major contributor to phototoxicity induced by FF taken orally, and this prediction was in accordance with the results from in vitro/in vivo phototoxicity tests. Results from this study suggest that this new screening strategy for parent substances and their metabolites provides reliable photosafety information on drug candidates and would be useful for drug development with wide safety margins.
- Kato, Masashi,Suzuki, Gen,Ohtake, Hiroto,Seto, Yoshiki,Onoue, Satomi
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p. 1815 - 1822
(2015/11/16)
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- DRUG DERIVATIVES
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The present invention relates to derivatives of known active pharmaceutical compounds. These derivatives are differentiated from the parent active compound by virtue of being redox derivatives of the active compound. This means that one or more of the functional groups in the active compound has been converted to another group in one or more reactions which may be considered to represent a change of oxidation state. We refer to these compounds generally as redox derivatives. The derivatives of the invention may be related to the original parent active pharmaceutical compound by only a single step transformation, or may be related via several synthetic steps including one or more changes of oxidation state. In certain cases, the functional group obtained after two or more transformations may be in the same oxidation state as the parent active compound (and we include these compounds in our definition of redox derivatives). In other cases, the oxidation state of the derivative of the invention may be regarded as being different from that of the parent compound. In many cases, the compounds of the invention have inherent therapeutic activity on their own account. In some cases, this activity relative to the same target or targets of the parent compound is as good as or better than the activity which the parent compound has against the target or targets.
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Paragraph 0268; 0269
(2013/09/12)
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- DRUG DERIVATIVES
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The present invention relates to derivatives of known active pharmaceutical compounds. These derivatives are differentiated from the parent active compound by virtue of being redox derivatives of the active compound. This means that one or more of the functional groups in the active compound has been converted to another group in one or more reactions which may be considered to represent a change of oxidation state. We refer to these compounds generally as redox derivatives. The derivatives of the invention may be related to the original parent active pharmaceutical compound by only a single step transformation, or may be related via several synthetic steps including one or more changes of oxidation state. In certain cases, the functional group obtained after two or more transformations may be in the same oxidation state as the parent active compound (and we include these compounds in our definition of redox derivatives). In other cases, the oxidation state of the derivative of the invention may be regarded as being different from that of the parent compound. In many cases, the compounds of the invention have inherent therapeutic activity on their own account. In some cases, this activity relative to the same target or targets of the parent compound is as good as or better than the activity which the parent compound has against the target or targets.
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Page/Page column 83-84
(2012/05/31)
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- TREATMENT OF METABOLIC SYNDROME WITH NOVEL AMIDES
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The present invention relates to the treatment of metabolic syndrome or disorders associated with metabolic syndrome comprising administering a compound of the invention.
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Page/Page column 81-82
(2009/07/17)
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- A mild hydrolysis of esters mediated by lithium salts
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When treated with amine bases such as triethylamine and various lithium salts in wet solvents, esters are efficiently hydrolyzed to the corresponding acids in good yields. Esters incorporating an α- or β-heteroatom with respect to the ester carbonyl group are hydrolyzed rapidly even at room temperature. To further demonstrate the usefulness of this method, one example is provided where hydrolysis of acetylated camphorsultam is mediated by LiBr.
- Mattsson, Sara,Dahlstr?m, Mikael,Karlsson, Staffan
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p. 2497 - 2499
(2007/10/03)
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- Liquid-phase synthesis of 2-methyl-2-aryloxypropanoic acid derivatives from poly(ethylene glycol) supported 2-bromo-2-methylpropanoate
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An efficient liquid-phase synthesis of 2-methyl-2-aryloxypropanoic acid derivatives with good yields and high purity on soluble polyethylene glycol (PEG) has been developed by treatment of PEG-bound 2-bromo-2-methylpropanoate with phenoxides in the presence of a catalytic amount of NBu4I and KI, and subsequent cleavage from the PEG.
- Huang, Bin,Huang, Pei-Gang,Sheng, Shou-Ri,Wang, Qiu-Ying,Guo, Lei,Jiang, Shao-Hua
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p. 575 - 578
(2008/02/11)
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- Spectrophotometric and liquid chromatographic determination of fenofibrate and vinpocetine and their hydrolysis products
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Several spectrophotometric and HPLC methods are presented for the determination of fenofibrate, vinpocetine and their hydrolysis products. The resolution of either fenofibrate or vinpocetine and their hydrolysis products has been accomplished by using numerical spectrophotometric methods as partial least squares (PLS-1) and principal component regression (PCR) applied to UV spectra; and graphical spectrophotometric methods as first derivative of ratio spectra (1DD) or first (1D) and second (2D) derivative spectrophotometry for vinpocetine and fenofibrate, respectively. In addition HPLC methods were developed using ODS column with mobile phase consisting of acetonitrile-water (80:20, v/v, pH 4) with UV detection at 287:nm for fenofibrate and a mobile phase consisting of acetonitrile-10:mM KH 2PO4, containing 0.1% diethylamine (60:40, v/v, pH:4.6) with UV detection at 270:nm for vinpocetine. The proposed methods were successfully applied for the determination of each drug and its hydrolysis product in laboratory-prepared mixture and pharmaceutical preparation. The proposed HPLC and derivative spectrophotometric methods were used to investigate the kinetics of acidic and alkaline hydrolytic processes of each drug. The pH-rate profile of hydrolysis of each drug in Britton-Robinson buffer solutions was studied.
- El-Gindy, Alaa,Emara, Samy,Mesbah, Mostafa K.,Hadad, Ghada M.
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p. 425 - 438
(2007/10/03)
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- AMINO ACID PRODRUGS
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The present invention is directed to a prodrug comprised of an amino acid bonded to a medicament or drug having a hydroxy, amino, carboxy or acylating derivative thereon. The prodrug has the same utility as the drug from which it is made, but it has enhanced therapeutic properties. In fact, the prodrugs of the present invention enhance at least two therapeutic qualities, as defined herein. The present invention is also directed to pharmaceutical compositions containing same.
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Page/Page column 176-177
(2008/06/13)
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- Improved method for the synthesis of 2-methyl-2-aryloxypropanoic acid derivatives
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An improved method for the formation of 2-methyl-2-aryloxypropanoic acid derivatives, an important class of compounds for the potential treatment of type II diabetes, is reported. This method offers several advantages over the existing chemistry for this transformation.
- Davis, Roman D.,Fitzgerald, Russ N.,Guo, Jiasheng
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p. 1959 - 1962
(2007/10/03)
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- A laser flash photolysis study of fenofibric acid in aqueous buffered media: Unexpected triplet state inversion in a derivative of 4-alkoxybenzophenone
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Laser excitation of aqueous solutions of fenofibric acid (FA) at pH 7.4 show the formation of two reaction intermediates, the triplet state and the hydrated electron. The former is longer lived in water than in acetonitrile; its anionic form decays irreve
- Cosa, Gonzalo,Purohit,Scaiano,Bosca, Francisco,Miranda, Miguel A.
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p. 193 - 200
(2007/10/03)
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