Pharmacophore-based discovery of 2-(phenylamino)aceto-hydrazides as potent eosinophil peroxidase (EPO) inhibitors

Journal of Enzyme Inhibition and Medicinal Chemistry

Paul G. Furtmüller¹  Thierry Langer²  Daniela Schuster³  Andreas Kubin⁴  Martina Zederbauer⁴ 

[1] Department of Chemistry, Division of Biochemistry, University of Natural Resources and Life Sciences, Vienna, Austri;Department of Pharmaceutical Chemistry, Division of Drug Design and Medicinal Chemistry, Faculty of Life Sciences, University of Vienna, Vienna, Austria;Institute of Pharmacy, Division of Pharmaceutical and Medicinal Chemistry, Paracelsus Medical Private University Salzburg, Salzburg, Austria;Planta Naturstoffe, Vienna, Austria;

关键词: Eosinophil peroxidase inhibitors;    2-(phenylamino)aceto-hydrazides derivatives;    mechanism of inhibition;    structure-activity-relationship;    pre-steady-state kinetics;   

DOI  :  10.1080/14756366.2018.1512598

来源: publisher

【 摘 要 】

There is an increasing interest in developing novel eosinophil peroxidase (EPO) inhibitors, in order to provide new treatment strategies against chronic inflammatory and neurodegenerative diseases caused by eosinophilic disorder. Within this study, a ligand-based pharmacophore model for EPO inhibitors was generated and used for in silico screening of large 3 D molecular structure databases, containing more than 4 million compounds. Hits obtained were clustered and a total of 277 compounds were selected for biological assessment. A class of 2-(phenyl)amino-aceto-hydrazides with different substitution pattern on the aromatic ring was found to contain the most potent EPO inhibitors, exhibiting IC50 values down to 10 nM. The generated pharmacophore model therefore, represents a valuable tool for the selection of compounds for biological testing. The compounds identified as potent EPO inhibitors will serve to initiate a hit to lead and lead optimisation program for the development of new therapeutics against eosinophilic disorders.

【 授权许可】

CC BY