1160741-77-4Relevant academic research and scientific papers
Tetrafluorophenoxymethyl ketone cruzain inhibitors with improved pharmacokinetic properties as therapeutic leads for Chagas' disease
Neitz, R. Jeffrey,Bryant, Clifford,Chen, Steven,Gut, Jiri,Hugo Caselli, Estefania,Ponce, Servando,Chowdhury, Somenath,Xu, Haichao,Arkin, Michelle R.,Ellman, Jonathan A.,Renslo, Adam R.
, p. 4834 - 4837 (2015/10/28)
Inhibition of the cysteine protease cruzain from Trypanosoma cruzi has been studied pre-clinically as a new chemotherapeutic approach to treat Chagas' disease. Efficacious effects of vinylsulfone-based cruzain inhibitors in animal models support this therapeutic hypothesis. More recently, substrate-activity screening was used to identify nonpeptidic tetrafluorophenoxymethyl ketone inhibitors of cruzain that showed promising efficacy in animal models. Herein we report efforts to further optimize the in vitro potency and in vivo pharmacokinetic properties of this new class of cruzain inhibitors. Through modifications of the P1, P2 and/or P3 positions, new analogs have been identified with reduced lipophilicity, enhanced potency, and improved oral exposure and bioavailability.
Nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors as promising new leads for chagas disease chemotherapy
Brak, Katrien,Kerr, Iain D.,Barrett, Kimberly T.,Fuchi, Nobuhiro,Debnath, Moumita,Ang, Kenny,Engel, Juan C.,McKerrow, James H.,Doyle, Patricia S.,Brinen, Linda S.,Ellman, Jonathan A.
experimental part, p. 1763 - 1773 (2010/08/20)
A century after discovering that the Trypanosoma cruzi parasite is the etiological agent of Chagas disease, treatment is still plagued by limited efficacy, toxicity, and the emergence of drug resistance. The development of inhibitors of the major T. cruzi cysteine protease, cruzain, has been demonstrated to be a promising drug discovery avenue for this neglected disease. Here we establish that a nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitor substantially ameliorates symptoms of acute Chagas disease in a mouse model with no apparent, toxicity. A high-resolution crystal structure confirmed the mode of inhibition and revealed key binding interactions of this novel inhibitor class. Subsequent structure-guided optimization then resulted in inhibitor analogues with improvements in potency despite minimal or no additions in molecular weight. Evaluation of the analogues in cell culture showed enhanced activity. These results suggest that nonpeptidic tetrafluorophenoxymethyl, ketone cruzain inhibitors have the potential to fulfill the urgent need for improved Chagas disease chemotherapy.
