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.
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.
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 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.
