Mechanism of action: Myeloperoxidase (MPO) inhibitor

Preclinical pharmacology

AZD5904 is a potent (IC50 of 140nM), irreversible inhibitor of human MPO with similar potency in mouse and rat. It is 10 to 19-fold selective compared to the closely related lactoperoxidase and thyroid peroxidase; >70-fold to a broad panel of other enzymes, ion channels, and receptors. In isolated human neutrophils, 1μM inhibited PMA stimulated HOCl by >90%. In rats, a plasma concentration of ~5μM decreased the in vivo formation of glutathione sulphonamide (a product of the reaction of HOCl with glutathione) from in situ zymosan activated peritoneum neutrophils.

Safety and tolerability

AZD5904 has been administered orally to healthy volunteers in single doses of up to 1200mg (1400mg with extended release, ER, formulation) and multiple doses of up to 325mg TID (600mg BID for 10 days with ER formulation). In total, 181 subjects have been dosed in five Phase 1 studies. No overtly drug-related adverse event has yet been identified, although a minimal effect on free P-Thyroxin (T4) and free P-Triiodothyronine (T3) could not be ruled out in the first multiple ascending dose study.

Preclinical studies of up 12 months duration have been performed.

Clinical pharmacology

Via both standard (TID) and extended release (BID) oral formulations, 300mg yielded blood concentrations of ~30uM peak, ~4uM trough, and 12-16μM Cavg. The main route of clearance is renal, possibly via active transport. Plasma protein binding is 44%. In vitro studies indicate CYP2C19 inhibition and P-gp substrate as well as low BBB penetration.

Suitable for and exclusions

The reproductive toxicology package indicates a risk of foetal toxicity. The inclusion of women of child-bearing potential would need to be assessed for any proposal based on the risk benefit and the use of appropriate highly effective contraception.

AZD5904 is renally cleared, thus, requiring caution and PK monitoring if dosed to subjects with impaired renal function.

Proposals will be considered for any therapeutic areas except neuroscience and CVRM related disease indications at this time

Additional information

Publications for this compound

The Journal of Biological Chemistry

2-Thioxanthines Are Mechanism-based Inactivators of Myeloperoxidase That Block Oxidative Stress during Inflammation

Gene information from the NCBi

This compound works on the following genes: