364794-80-9Relevant articles and documents
Bis(het)aryl-1,2,3-triazole quinuclidines as α7 nicotinic acetylcholine receptor ligands: Synthesis, structure affinity relationships, agonism activity, [18F]-radiolabeling and PET study in rats
Ouach, Aziz,Vercouillie, Johnny,Bertrand, Emilie,Rodrigues, Nuno,Pin, Frederic,Serriere, Sophie,Boiaryna, Liliana,Chartier, Agnes,Percina, Nathalie,Tangpong, Pakorn,Gulhan, Zuhal,Mothes, Celine,Deloye, Jean-Bernard,Guilloteau, Denis,Page, Guylene,Suzenet, Franck,Buron, Frederic,Chalon, Sylvie,Routier, Sylvain
, p. 449 - 469 (2019/07/03)
In this paper we describe the design and synthesis of bis(Het)Aryl-1,2,3-triazole quinuclidine α7R ligands using an efficient three-step sequence including a Suzuki-Miyaura cross coupling reaction with commercially available and home-made boron derivatives. The exploration of SAR required the preparation of uncommon boron derivatives. Forty final drugs were tested for their ability to bind the target and nine of them exhibited Ki values below nanomolar concentrations. The best scores were always obtained when the 5-phenyl-2-thiophenyl core was attached to the triazole. The selectivity of these compounds towards the nicotinic α4β2 and serotoninergic 5HT3 receptors was assessed and their brain penetration was quantified by the preparation and in vivo evaluation of two [18F] radiolabelled derivatives. It can be expected from our results that some of these compounds will be suitable for further developments and will have effects on cognitive disorders.
Kinase scaffold repurposing for neglected disease drug discovery: Discovery of an efficacious, lapatanib-derived lead compound for trypanosomiasis
Patel, Gautam,Karver, Caitlin E.,Behera, Ranjan,Guyett, Paul J.,Sullenberger, Catherine,Edwards, Peter,Roncal, Norma E.,Mensa-Wilmot, Kojo,Pollastri, Michael P.
supporting information, p. 3820 - 3832 (2013/06/27)
Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei. Because drugs in use against HAT are toxic and require intravenous dosing, new drugs are needed. Initiating lead discovery campaigns b
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%.
