title: Structure-metabolism relationships inhuman-AOX: Chemical insights from a large database of aza-aromatic and amide compounds.
abstract: Aldehyde oxidase (AOX) is a metabolic enzyme catalyzing the oxidation of aldehyde and aza-aromatic compounds and the hydrolysis of amides, moieties frequently shared by the majority of drugs. Despite its key role in human metabolism, to date only fragmentary information about the chemical features responsible for AOX susceptibility are reported and only "very local" structure-metabolism relationships based on a small number of similar compounds have been developed. This study reports a more comprehensive coverage of the chemical space of structures with a high risk of AOX phase I metabolism in humans. More than 270 compounds were studied to identify the site of metabolism and the metabolite(s). Both electronic [supported by density functional theory (DFT) calculations] and exposure effects were considered when rationalizing the structure-metabolism relationship.
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy.
authors.forename: Susan
authors.identifier: 0000-0003-1024-7368
authors.initials: S
authors.lastname: Lepri
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Ceccarelli
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy.
authors.forename: Nicolò
authors.initials: N
authors.lastname: Milani
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Tortorella
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cucco
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy.
authors.forename: Aurora
authors.identifier: 0000-0003-4027-7613
authors.initials: A
authors.lastname: Valeri
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Goracci
authors.affiliation: Roche Pharma Research and Early Development, Drug Disposition and Safety, Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd., 4070 Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Brink
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy; gabriele.cruciani@unipg.it.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cruciani
mesh_terms: D042931:Aldehyde Oxidase / Q000737:chemistry* / Q000378:metabolism*; D000577:Amides / Q000737:chemistry*; D001372:Aza Compounds / Q000737:chemistry*; D055162:Biocatalysis; D062313:Databases, Pharmaceutical; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000737:chemistry*; D010084:Oxidation-Reduction; D011487:Protein Conformation; D013379:Substrate Specificity
chemical_list: D000577:Amides; D001372:Aza Compounds; D006841:Hydrocarbons, Aromatic; C526436:AOX1 protein, human; D042931:Aldehyde Oxidase
keywords: aldehyde oxidase; amide hydrolysis; site of metabolism; structure–metabolism relationship; variously decorated heterocycles