1011726-66-1Relevant articles and documents
Chemical-biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-target
Choy, Jonathan W.,Bryant, Clifford,Calvet, Claudia M.,Doyle, Patricia S.,Gunatilleke, Shamila S.,Leung, Siegfried S. F.,Ang, Kenny K. H.,Chen, Steven,Gut, Jiri,Oses-Prieto, Juan A.,Johnston, Jonathan B.,Arkin, Michelle R.,Burlingame, Alma L.,Taunton, Jack,Jacobson, Matthew P.,McKerrow, James M.,Podust, Larissa M.,Renslo, Adam R.
supporting information, p. 15 - 25 (2013/04/10)
Inhibition of the Trypanosoma cruzi cysteine protease cruzain has been proposed as a therapeutic approach for the treatment of Chagas' disease. Among the best-studied cruzain inhibitors to date is the vinylsulfone K777 (1), which has proven effective in animal models of Chagas' disease. Recent structure-activity studies aimed at addressing potential liabilities of 1 have now produced analogues such as N-[(2S)-1-[[(E,3S)-1-(benzenesulfonyl)-5- phenylpent-1-en-3-yl]amino]-3-(4-methylphenyl)-1- oxopropan-2-yl]pyridine-4- carboxamide (4), which is trypanocidal at ten-fold lower concentrations than for 1. We now find that the trypanocidal activity of 4 derives primarily from the inhibition of T. cruzi 14-a-demethylase (TcCYP51), a cytochrome P450
