title: Medicinal chemistry approaches to avoid aldehyde oxidase metabolism.
abstract: Aldehyde oxidase (AO) is a molybdenum-containing enzyme distributed throughout the animal kingdom and capable of metabolising a wide range of aldehydes and N-heterocyclic compounds. Although metabolism by this enzyme in man is recognised to have significant clinical impact where human AO activity was not predicted by screening in preclinical species, there is very little reported literature offering real examples where drug discoverers have successfully designed away from AO oxidation. This article reports on some strategies adopted in the Pfizer TLR7 agonist programme to successfully switch off AO metabolism that was seen principally in the rat.
authors.affiliation: Worldwide Medicinal Chemistry, Dynamics and Metabolism, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent, UK. David.Pryde@pfizer.com
authors.forename: David C
authors.initials: DC
authors.lastname: Pryde
authors.forename: Thien-Duc
authors.initials: TD
authors.lastname: Tran
authors.forename: Peter
authors.initials: P
authors.lastname: Jones
authors.forename: Jonathan
authors.initials: J
authors.lastname: Duckworth
authors.forename: Martin
authors.initials: M
authors.lastname: Howard
authors.forename: Iain
authors.initials: I
authors.lastname: Gardner
authors.forename: Ruth
authors.initials: R
authors.lastname: Hyland
authors.forename: Rob
authors.initials: R
authors.lastname: Webster
authors.forename: Tracey
authors.initials: T
authors.lastname: Wenham
authors.forename: Sharan
authors.initials: S
authors.lastname: Bagal
authors.forename: Kiyoyuki
authors.initials: K
authors.lastname: Omoto
authors.forename: Richard P
authors.initials: RP
authors.lastname: Schneider
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
mesh_terms: D042931:Aldehyde Oxidase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D003600:Cytosol / Q000201:enzymology; D004285:Dogs; D004355:Drug Stability; D006801:Humans; D008297:Male; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship; D051199:Toll-Like Receptor 7 / Q000819:agonists
chemical_list: D011725:Pyridines; C489639:TLR7 protein, rat; D051199:Toll-Like Receptor 7; D042931:Aldehyde Oxidase