AZD5904
Preclinical pharmacology
AZD5904 is a potent, irreversible inhibitor of human MPO with similar potency in mouse and rat.
| Potency (IC50) | 140nM |
| Selectivity | 10-19 fold greater than for lactoperoxidase and thyroid peroxidase. >70-fold to a broad panel of other enzymes, ion channels, and receptors. |
| In vitro functionality | 1μM inhibited PMA stimulated HOCl by >90% in isolated human neurotrophils |
| In vivo functionality (rat) | ~5μM plasma concentration decreased glutathione sulphonamide formation 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 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
Standard (TID) and extended release (BID) oral formulations, at 300mg yielded blood concentrations of ~30μM peak, ~4μM 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 and 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.
Mechanism of Action
Myeloperoxidase (MPO) inhibitor
Original Therapeutic Area
Other
CNS Penetrant
Low
Route of administration
Oral
Modality
Small Molecule
Additional Information
1. Campbell MJ., et al. (2021).
Myeloperoxidase inhibitor AZD5904 enhances human sperm function in vitro. Hum Reprod. Feb 18;36(3):560-570. doi: 10.1093/humrep/deaa328. PMID: 33393586.
2. Michaëlsson E., et al. (2019).
Inhibiting myeloperoxidase prevents onset and reverses established high-fat diet-induced microvascular insulin resistance. Am J Physiol Endocrinol Metab. Dec 1;317(6):E1063-E1069. doi: 10.1152/ajpendo.00203.2019. Epub 2019 Oct 8. PMID: 31593502.