99516-18-4Relevant academic research and scientific papers
Discovery of Potent, Reversible, and Competitive Cruzain Inhibitors with Trypanocidal Activity: A Structure-Based Drug Design Approach
De Souza, Mariana L.,De Oliveira Rezende Junior, Celso,Ferreira, Rafaela S.,Espinoza Chávez, Rocio Marisol,Ferreira, Leonardo L. G.,Slafer, Brian W.,Magalh?es, Luma G.,Krogh, Renata,Oliva, Glaucius,Cruz, Fabio Cardoso,Dias, Luiz Carlos,Andricopulo, Adriano D.
, p. 1028 - 1041 (2019/12/27)
A virtual screening conducted with nearly 4?000?000 compounds from lead-like and fragment-like subsets enabled the identification of a small-molecule inhibitor (1) of the Trypanosoma cruzi cruzain enzyme, a validated drug target for Chagas disease. Subsequent comprehensive structure-based drug design and structure-activity relationship studies led to the discovery of carbamoyl imidazoles as potent, reversible, and competitive cruzain inhibitors. The most potent carbamoyl imidazole inhibitor (45) exhibited high affinity with a Ki value of 20 nM, presenting both in vitro and in vivo activity against T. cruzi. Furthermore, the most promising compounds reduced parasite burden in vivo and showed no toxicity at a dose of 100 mg/kg. These carbamoyl imidazoles are structurally attractive, nonpeptidic, and easy to prepare and synthetically modify. Finally, these results further advance our understanding of the noncovalent mode of inhibition of this pharmaceutically relevant enzyme, building strong foundations for drug discovery efforts.
Arylaminoethyl amides as novel non-covalent cathepsin K inhibitors
Altmann, Eva,Renaud, Johanne,Green, Jonathan,Farley, David,Cutting, Brian,Jahnke, Wolfgang
, p. 2352 - 2354 (2007/10/03)
A series of Nα-benzyloxycarbonyl- and Nα-acyl-L-leucine(2-phenylaminoethyl)amide derivatives were prepared and evaluated for their inhibitory activity against rabbit and human cysteine proteases cathepsins K, L, and S. These data ind
