Metabolism by Aldehyde Oxidase: Drug Design and Complementary Approaches to Challenges in Drug Discovery

Journal of Medicinal Chemistry
Nenad ManevskiFrancesca Toselli

Abstract

Aldehyde oxidase (AO) catalyzes oxidations of azaheterocycles and aldehydes, amide hydrolysis, and diverse reductions. AO substrates are rare among marketed drugs, and many candidates failed due to poor pharmacokinetics, interspecies differences, and adverse effects. As most issues arise from complex and poorly understood AO biology, an effective solution is to stop or decrease AO metabolism. This perspective focuses on rational drug design approaches to modulate AO-mediated metabolism in drug discovery. AO biological aspects are also covered, as they are complementary to chemical design and important when selecting the experimental system for risk assessment. The authors' recommendation is an early consideration of AO-mediated metabolism supported by computational and in vitro experimental methods but not an automatic avoidance of AO structural flags, many of which are versatile and valuable building blocks. Preferably, consideration of AO-mediated metabolism should be part of the multiparametric drug optimization process, with the goal to improve overall drug-like properties.

References

Aug 1, 1979·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·C StubleyD W Mathieson
Oct 1, 1987·European Journal of Drug Metabolism and Pharmacokinetics·C BeedhamD J Rance
Mar 1, 1987·Archives of Biochemistry and Biophysics·K Tatsumi, M Ishigai
Jun 1, 1986·Archives of Biochemistry and Biophysics·K Sugihara, K Tatsumi
Apr 30, 1984·Biochemical and Biophysical Research Communications·S Kitamura, K Tatsumi
Dec 1, 1984·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·B KayeW S Hillis
May 1, 1984·Proceedings of the National Academy of Sciences of the United States of America·T A KrenitskyP D Whiteman
Jun 29, 1984·Biochemical and Biophysical Research Communications·S Kitamura, K Tatsumi
Dec 1, 1982·Chemical & Pharmaceutical Bulletin·K TatsumiH Yamada
Oct 26, 1995·Biochemical Pharmacology·S K RoyM E Dolan
Oct 29, 1993·Journal of Medicinal Chemistry·S M Firestine, V J Davisson
Nov 1, 1995·Biochemical Society Transactions·A M FowlerK Wilson
Oct 1, 1996·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·A A AcheampongD Tang-Liu
May 23, 1998·Advances in Experimental Medicine and Biology·Y MoriwakiK Higashino
Jun 29, 1999·The Journal of Pharmacy and Pharmacology·C G JordanC Beedham
Nov 24, 1999·The Journal of Biological Chemistry·W AmbroziakR Pietruszko
Mar 22, 2000·Journal of Agricultural and Food Chemistry·G J Diaz, E J Squires
Nov 7, 2002·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·B G LakeJ A Scatina
Jun 27, 2003·Journal of Clinical Psychopharmacology·Christine BeedhamR Scott Obach
Oct 25, 2003·Proceedings of the National Academy of Sciences of the United States of America·Francisco Rodríguez-TrellesFrancisco J Ayala
Dec 19, 2003·Journal of Clinical Pharmacology·R Scott ObachChristine Beedham
Jan 8, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·R Scott Obach
Jun 19, 2004·Journal of Drug Targeting·Remigijus DidziapetrisAlanas Petrauskas
Sep 9, 2004·Chemical Reviews·Bernard MeunierSason Shaik
Oct 19, 2004·Chemical Research in Toxicology·Georgios I PanoutsopoulosChristine Beedham
Jan 4, 2005·Pharmacology·Georgios I Panoutsopoulos, Christine Beedham
Feb 22, 2005·Chemical Research in Toxicology·Ryan A DickJohn E Casida

❮ Previous
Next ❯

Citations

Jun 1, 2020·Clinical and Translational Science·Kei IrieTohru Hashida
Apr 5, 2020·Clinical Pharmacology and Therapeutics·Yin-Xiao Du, Xiao-Ping Chen
Nov 5, 2020·International Journal of Molecular Sciences·Masato OokaMenghang Xia
Mar 20, 2020·Journal of Medicinal Chemistry·Jihui ZhaoMingyue Zheng
Sep 12, 2020·Journal of Medicinal Chemistry·Christian Gampe, Vishal A Verma
May 5, 2021·Drug Metabolism Reviews·Nikhilesh V DhuriaJasleen K Sodhi
May 17, 2021·Journal of Pharmaceutical and Biomedical Analysis·Elias Carvalho PadilhaXin Xu
Jul 17, 2021·Bioorganic & Medicinal Chemistry Letters·Subramanyam VankadaraC S Brian Chia
Nov 21, 2020·ACS Medicinal Chemistry Letters·Julia Shanu-WilsonJason Boer
Nov 22, 2019·ACS Medicinal Chemistry Letters·Gilles OuvryLaurent F Hennequin
Jun 20, 2020·ACS Medicinal Chemistry Letters·Stephane PerreaultGary Phillips
Jun 30, 2021·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Claudia Garrido, Silke Leimkühler
Oct 16, 2021·ChemMedChem·C S Brian ChiaPearly Shuyi Ng

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antiparasitics

Antiparasitics are medications which are indicated for the treatment of parasitic diseases. Discover the latest research on antiparasitics here.

Related Papers

Annual Review of Biochemistry
K A C ELLIOTT
Annual Review of Biochemistry
H WEIL-MALHERBE
Annual Review of Biochemistry
L MICHAELIS
The New England Journal of Medicine
R J TempleJ R Crout
© 2021 Meta ULC. All rights reserved