title: Optimization of important early ADME(T) parameters of NADPH oxidase-4 inhibitor molecules.
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.
authors.affiliation: Pathobiochemistry Research Group of Hungarian Academy of Sciences, Department of Medical Chemistry, Semmelweis University, Budapest, Hungary. gabor.borbely@kkk.org.hu
authors.forename: Gábor
authors.initials: G
authors.lastname: Borbély
authors.forename: Ménika
authors.initials: M
authors.lastname: Huszár
authors.forename: Attila
authors.initials: A
authors.lastname: Varga
authors.forename: Krisztina
authors.initials: K
authors.lastname: Futosi
authors.forename: Attila
authors.initials: A
authors.lastname: Mócsai
authors.forename: László
authors.initials: L
authors.lastname: Orfi
authors.forename: Miklós
authors.initials: M
authors.lastname: Idei
authors.forename: József
authors.initials: J
authors.lastname: Mandl
authors.forename: György
authors.initials: G
authors.lastname: Kéri
authors.forename: Tibor
authors.initials: T
authors.lastname: Vántus
mesh_terms: D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human