Aldehyde oxidase metabolite toxicity
This month we highlight a paper describing a project in which toxicity arising from metabolite-mediated prolongation of coagulation was uncovered and overcome.
GDC-6599 is a transient receptor potential ankyrin 1 (TRPA1) antagonist currently in Phase II clinical trials for respiratory indications. Predecessor molecules to GDC-6599 were found to suffer from anticoagulation mediated toxicity. The toxicity was attributed to one of two circulating metabolites formed by aldehyde oxidase in monkey and human. This was exacerbated by the accumulation of the undesirable metabolite 2-M1 on repeat dosing. Metabolite 2-M1 possesses a hypoxanthine phamacophore similar to known anticoagulants. The resulting coagulopathy was proposed to result from disruption of the vitamin K redox cycle.
A relatively simple solution was implemented that blocked AO-mediated oxidation at the metabolic softspot to 2-M1 through installation of a methyl group at the 2-position. Methylation at this position completely blocked formation of 2-M1 whereas deuterium-substitution was only partially successful.Whilst methylation at the 2-position did not impact TRPA1 potency, adding a second methyl group at the 8-position to prevent both points of oxidation caused a dramatic drop in potency.
Despite blocking the metabolic soft spot through methylation, the prolongation in coagulation was not completely eliminated in vivo. The authors speculated that structural similarity of GDC-6599 to vitamin K and the potential overlap of their methyl groups in the binding site raised the possibility that GDC-6599 may be able to inhibit vitamin K epoxide reductase as part of the vitamin K redox cycle in vivo. However inhibition occurs at a considerably lower level compared to the predecessor compounds.
Paper (open access)
Terrett et al., 2024. Discovery of TRPA1 Antagonist GDC-6599: Derisking Preclinical Toxicity and Aldehyde Oxidase Metabolism with a Potential First-in-Class Therapy for Respiratory Disease. Journal of Medicinal Chemistry, 67 (5), 3287-3306 DOI: 10.1021/acs.jmedchem.3c0212