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 (ELUMO)], 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 ELUMO). 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.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
- AO
- aldehyde oxidase
- LUMO
- lowest unoccupied molecular orbitals
- ELUMO
- energy of lowest unoccupied molecular orbitals
- DMSO
- dimethyl sulfoxide
- HPLC
- high-performance liquid chromatography
- MS
- mass spectrometry
- ESP
- electrostatic potential
- ΔG
- energy for the formation of tetrahedral intermediate in the oxygenation of substrate
- MoCo
- molybdenum pyranopterin cofactor moiety
- XDH
- xanthine dehydrogenase
- au
- atomic units.
- Received March 22, 2012.
- Accepted May 15, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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