Optimization of Important Early ADME(T) Parameters of NADPH Oxidase-4 Inhibitor Molecules

Gabor Borbely, Monika Huszar, Attila Varga, Krisztina Futosi, Attila Mocsai, Laszlo Orfi, Miklos Idei, Jozsef Mandl; Gyorgy Keri, Tibor Vantus

doi:10.2174/157340612800493674

Abstract

Through their reactive oxygen species (ROS) producing function, NADPH oxidase (NOX) enzymes have been linked to several oxidative stress related diseases. In our recently published paper [1] we have already shown the NOX4 inhibitory effect of diverse, molecule sub-libraries and their biological importance. We also presented our work connected to potential anti-tumour molecules and the relationship between their biological activity and physico-chemical properties [2]. As an extension of these studies further physico-chemical and biological investigation has been carried out on a molecule group included NOX4 inhibitory chromanone compounds. Here we describe the optimization of early ADME(T) parameters determining lipophilicity, phospholipophilicity and permeability linked to structure-activity relationship. We prove that optimal lipo- and phospholipophilicty can be also determined in case of NOX4 inhibitors and a comparison will be made between the chemically similar isochromanone and chromanone molecular libraries. It will be also shown how to predict the effect of different substituents on permeability, lipo- and phospholipophilicity and also the biological differences between anti-tumour molecules and NOX4 inhibitors according to their penetration ability.

Keywords: ADME(T), haracterization, compounds, disease, inhibitor, NADPH oxidase 4, relationship, species, enzymes, stress