Mechanism of action: Histamine receptor 3 (H3) antagonist (inverse agonist)

Preclinical pharmacology

AZD5213 is potent (Ki 0.5nM; dissociation KB 0.2nM), competitive, rapidly reversible, functional antagonist (inverse agonist; IC50 of 3nM) at the human H3 receptor. It occupies H3 receptors with an in vivo pKi of 8.5, 8.3 and 8.4 (free concentration in brain) for rat, mouse and NHP, respectively. AZD5213 was tested against a broad panel of 335 other receptors and enzymes at 10μM without significant activity (>50% inhibition) for any. In vivo, it triggers the release of histamine as well as the neurotransmitters acetylcholine, dopamine and norepinephrine in rat prefrontal cortex following dosing or 0.33mg/kg, po and increased tele-methylhistamine in the CSF of cynomolgus monkeys at 0.1mg/kg, po. At similar dose levels, AZD5213 has been shown to reverse scopolamine-induced memory deficit, increase novel object recognition, and reverse neuropathic in various rodent models.

Safety and tolerability

AZD5213 has been administered orally to healthy volunteers in single doses up to 80mg and multiple doses up to 18mg QD for 10 days. The most frequent and dosing limiting adverse effects were sleep disorder, night sweats, and decreased quantity as well as quality of sleep. Other common AEs include mild to moderate nausea and headache.

Preclinical studies of up to 6 months duration have been performed.

Clinical pharmacology

AZD5213 was rapidly absorbed (Tmax of 0.7-2.0 hrs) after oral administration with an overall terminal t½ of 5-7 hours. In vitro studies show a low risk for DDIs. PET studies demonstrated saturable, concentration-dependent occupancy of H3 receptors with an estimated Ki,pl of 1.14nM. Receptor occupancy of ~50% was achieved at a dose of 0.1mg.

Suitable for and exclusions

Preclinical reprotoxicology data are available and have not identified any specific risks. Women of child-bearing potential using highly effective contraception can be included.

Indications and dosing regimen should consider the potential for and optimisation of efficacy while minimizing the mechanism-based adverse effect on sleep. Given the strong association between dose, plasma concentration and brain receptor occupancy as well as the rapid absorption and relatively short t½, data is available to potentially optimise benefit (day time efficacy) versus risk (night time sleep disturbance).

Additional Information

Clinical trials for this compound

See all of the clinical trials currently associated with this compound:

Publications for this compound

Find out more about this compound by reading related publications:

AZD5213: a novel histamine H3 receptor antagonist permitting high daytime and low nocturnal H3 receptor occupancy, a PET study in human subjects

Gene information from the NCBi

This compound works on the following genes: