- Design, synthesis and biological evaluation of biphenylamide derivatives as Hsp90 C-terminal inhibitors
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Modulation of Hsp90 C-terminal function represents a promising therapeutic approach for the treatment of cancer and neurodegenerative diseases. Current drug discovery efforts toward Hsp90 C-terminal inhibition focus on novobiocin, an antibiotic that was transformed into an Hsp90 inhibitor. Based on structural information obtained during the development of novobiocin derivatives and molecular docking studies, scaffolds containing a biphenyl moiety in lieu of the coumarin ring present in novobiocin were identified as new Hsp90 C-terminal inhibitors. Structure-activity relationship studies produced new derivatives that inhibit the proliferation of breast cancer cell lines at nanomolar concentrations, which corresponded directly with Hsp90 inhibition.
- Zhao, Huiping,Garg, Gaurav,Zhao, Jinbo,Moroni, Elisabetta,Girgis, Antwan,Franco, Lucas S.,Singh, Swapnil,Colombo, Giorgio,Blagg, Brian S.J.
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- BIPHENYLAMIDE DERIVATIVE HSP90 INHIBITORS
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Compounds of the formulas are provided: wherein variables Y1-Y5, X1-X5, A1-A4, x, y, n1, n2, and R1-R15 are as defined herein. Pharmaceutical compositions of the compounds are also provided. In some aspects, these compounds are are useful for the treatment of a disease or disorder, including, for example, a proliferative disease, such as cancer.
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Page/Page column 99
(2015/05/26)
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- Solubility-driven optimization of (pyridin-3-yl) benzoxazinyl- oxazolidinones leading to a promising antibacterial agent
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The solubility-driven structural modification of (pyridin-3-yl) benzoxazinyl-oxazolidinones is described, which resulted in the development of a new series of benzoxazinyl-oxazolidinone analogues with high antibacterial activity against Gram-positive pathogens, including that against linezolid-resistant strains and low hERG inhibition. With regard to structure-activity relationship (SAR) trends among the various substituents on the pyridyl ring, relatively small and nonbasic substituents were preferable to sterically demanding or basic substituents. Oxazolidinone ring substitution on the pyridyl ring generated analogues with antibacterial activity superior to imidazolidinone ring. Solubility was enhanced by the incorporation of polar groups, especially when compounds were converted to their prodrugs. Among the prodrugs, compound 85 exhibited excellent solubility and a good pharmacokinetic profile. In a MRSA systemic infection model, compound 85 displayed an ED 50 = 5.00 mg/kg, a potency that is 2-fold better than that of linezolid.
- Guo, Bin,Fan, Houxing,Xin, Qisheng,Chu, Wenjing,Wang, Hui,Huang, Yanqin,Chen, Xiaoyan,Yang, Yushe
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supporting information
p. 2642 - 2650
(2013/05/09)
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- PYRROLE DERIVATIVES USEFUL FOR THE TREATMENT OF CYTOKINE-MEDIATED DISEASES
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A compound of Formula (I) or a pharmaceutically acceptable salt or prodrug ester thereof, wherein the groups R1-R6 and A are as defined in the specification.
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Page/Page column 105-106
(2008/06/13)
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