AZD5213
Preclinical pharmacology
AZD5213 is potent, competitive, rapidly reversible, functional antagonist (inverse agonist) at the human H3 receptor.
| Potency (Ki)/KB | 0.5nM/0.2nM |
| Activity (IC50) | 3nM |
| In vivo occupancy of H3 receptor (pKi) (rat, mouse, NHP) | 8.5, 8.3 and 8.4 (free concentration in brain) |
| Selectivity | >10μM for 335 receptors and enzymes |
In vivo, AZD5213 triggers the release of histamine and the neurotransmitters acetylcholine, dopamine and norepinephrine in rat prefrontal cortex following dosing at 0.33mg/kg, po. Increased tele-methylhistamine in the CSF of cynomolgus monkeys was observed 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 pain 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 (AEs) were sleep disorder, night sweats, and decreased quantity and 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 0.7-2.0hrs) after oral administration with an overall terminal t½ of 5-7 hours. In vitro studies showed 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).
Mechanism of Action
Histamine receptor 3 antagonist (inverse agonist)
Original Therapeutic Area
Neuroscience
CNS Penetrant
Yes
Route of administration
Oral
Modality
Small Molecule
Additional Information
1. Alexander RC., et al. (2021).
A 3-way Cross-over Study of Pregabalin, Placebo, and the Histamine 3 Receptor Inverse Agonist AZD5213 in Combination With Pregabalin in Patients With Painful Diabetic Neuropathy and Good Pain-reporting Ability. Clin J Pain. Jan;37(1):38-42. doi: 10.1097/AJP.0000000000000886. PMID: 33086238.
2. Jucaite A., et al. (2013).
AZD5213: a novel histamine H3 receptor antagonist permitting high daytime and low nocturnal H3 receptor occupancy, a PET study in human subjects. Int J Neuropsychopharmacol. Jul;16(6):1231-9. doi: 10.1017/S1461145712001411. PMID: 23217964.