title: Effect of structural variation on aldehyde oxidase-catalyzed oxidation of zoniporide.
abstract: Current studies explored the effect of structural changes on the aldehyde oxidase (AO)-mediated metabolism of zoniporide (1). Zoniporide analogs with modifications of the acylguanidine moiety, the cyclopropyl group on the pyrazole ring, and the quinoline ring were studied for their AO-catalyzed metabolism using the human S9 fraction. Analysis of the half-lives suggested that subtle changes in the structure of 1 influenced its metabolism and that the guanidine and the quinoline moieties were prerequisites for AO-catalyzed oxidation to 2-oxozoniporide (M1). In contrast, replacement of the cyclopropyl group with other alkyl groups was tolerated. The effect of structural variation on AO properties was rationalized by docking 1 and its analogs into the human AO homology model. These studies indicated the importance of electrostatic, π-π stacking and hydrophobic interactions of the three motifs with residues in the active site. Differences in substrate properties were also rationalized by comparing their half-lives with cLogD, electrophilicity parameters [electrostatic potential (ESP) charges and energy of lowest unoccupied molecular orbitals (E(LUMO))], and the energies of formation of tetrahedral intermediates (J Med Chem 50:4642-4647, 2007). Whereas the success of energetics in predicting the AO substrate properties of analogs was 87%, the predictive ability of other descriptors was none (cLogD) to 60% (ESP charges and E(LUMO)). Overall, the structure-metabolism relationship could be rationalized using a combination of both the energy calculations and docking studies. This combination method can be incorporated into a strategy for mitigating AO liabilities observed in the lead candidate or studying structure-metabolism relationships of other AO substrates.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, San Diego, CA 92121, USA. deepak.dalvie@pfizer.com
authors.forename: Deepak
authors.initials: D
authors.lastname: Dalvie
authors.forename: Hao
authors.initials: H
authors.lastname: Sun
authors.forename: Cathie
authors.initials: C
authors.lastname: Xiang
authors.forename: Qiyue
authors.initials: Q
authors.lastname: Hu
authors.forename: Ying
authors.initials: Y
authors.lastname: Jiang
authors.forename: Ping
authors.initials: P
authors.lastname: Kang
mesh_terms: D042931:Aldehyde Oxidase / Q000378:metabolism*; D055162:Biocatalysis; D002851:Chromatography, High Pressure Liquid; D006146:Guanidines / Q000378:metabolism*; D006207:Half-Life; D007700:Kinetics; D008958:Models, Molecular; D010084:Oxidation-Reduction; D011720:Pyrazoles / Q000378:metabolism*
chemical_list: D006146:Guanidines; D011720:Pyrazoles; C424422:zoniporide; D042931:Aldehyde Oxidase