Jonathan S. Foot
Jonathan completed his PhD at the University of York in 2005 and has held postdoctoral positions at the University of Toronto (2009) and the Australian National University (2006). Jonathan is a Senior Research Scientist at Pharmaxis Ltd in Sydney Australia where he works in the drug discovery department with roles in medicinal chemistry, computer-aided drug design and project managment.
Human membrane primary amine oxidase (hAOC3, also known as vascular adhesion protein-1, VAP-1) is a member of the copper dependent amine oxidase family. The enzymatic function of this protein is commonly known as Semicarbazide Sensitive Amine Oxidase (SSAO), and has been shown to play a crucial role in leukocyte rolling, adhesion and migration in various disease models. The binding site of this enzyme contains a topaquinone co-factor, derived from a modified tyrosine residue, that catalyses the oxidative deamination of primary amines to aldehydes with co-committal release ammonia and hydrogen peroxide. As part of our ongoing research into inflammatory lung diseases, we decided to target this enzyme using a mechanism-based inhibitor approach. Here we present the various challenges we have had to address during development including design, selectivity over related amine oxidases, in vitro cell health considerations and most significantly, optimisation of our molecules to be true mechanism-based inhibitors with no substrate turnover. The influence of in vitro SAR profiling and computer aided drug design will be discussed.