18979-62-9Relevant articles and documents
Discovery and SAR study of hydroxyacetophenone derivatives as potent, non-steroidal farnesoid X receptor (FXR) antagonists
Liu, Peng,Xu, Xing,Chen, Lili,Ma, Lei,Shen, Xu,Hu, Lihong
, p. 1596 - 1607 (2014/03/21)
Compound 1 (IC50 = 35.2 ± 7.2 μM), a moderate FXR antagonist was discovered via high-throughput screening. Structure-activity relationship studies indicated that the shape and the lipophilicity of the substituents of the aromatic ring affect the activity dramatically, increasing the shape and the lipophilicity of the substituents of the aromatic ring enhances the potency of FXR antagonists. Especially, when the OH at C2 position of the aromatic ring was replaced by the OBn substituent (analog 2b), its activity could be improved to IC50 = 1.1 ± 0.1 μM. Besides, the length of the linker and the tetrazole structure are essential for retaining the activity.
4,5-Diarylisoxazole Hsp90 chaperone inhibitors: Potential therapeutic agents for the treatment of cancer
Brough, Paul A.,Aherne, Wynne,Barril, Xavier,Borgognoni, Jenifer,Boxall, Kathy,Cansfield, Julie E.,Cheung, Kwai-Ming J.,Collins, Ian,Davies, Nicholas G. M.,Drysdale, Martin J.,Dymock, Brian,Eccles, Suzanne A.,Finch, Harry,Fink, Alexandra,Hayes, Angela,Howes, Robert,Hubbard, Roderick E.,James, Karen,Jordan, Allan M.,Lockie, Andrea,Martins, Vanessa,Massey, Andrew,Matthews, Thomas P.,McDonald, Edward,Northfield, Christopher J.,Pearl, Laurence H.,Prodromou, Chrisostomos,Ray, Stuart,Raynaud, Florence I.,Roughley, Stephen D.,Sharp, Swee Y.,Surgenor, Allan,Walmsley, D. Lee,Webb, Paul,Wood, Mike,Workman, Paul,Wright, Lisa
, p. 196 - 218 (2008/09/17)
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure - activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by ～50%.
