AZD0284
Preclinical Pharmacology & Pharmacokinetics
AZD0284 is an inverse agonist of the human nuclear Retinoic Acid-Related Orphan Receptor (RORɣ). Experiments in vivo demonstrated that AZD0284 inhibited the function of RORɣ and reduced the frequency and numbers of IL-17A producing cells in a mouse model of skin inflammation. Potency is similar across species with pIC50 of 7.4, 7.9, 7.1, 7.7, and 7.8 across human, dog, mouse, rat, and rabbit RORɣ respectively. AZD0284 is selective for RORɣ vs. RORα or RORβ up to 5μM.
Safety & tolerability profile
Preclinical studies in both rat and dog of up to one-month duration have been conducted. The NOAEL in rats was considered to be 500 mg/kg/day (250 mg/kg.bid) orally + 80 mg/kg/day subcutaneously. AZD0284 was well tolerated in dogs at levels of up to 250 mg/kg/day (125 mg/kg.bid), the steady state total Cmax exposure at the end of the repeat dose trials was 9.63±2.08 μM corresponding to a free exposure at 250 mg/kg/day of 1.22±0.26 μM.
Clinical pharmacology
Phase I clinical studies in healthy participants have been completed for AZD0284(NCT02976831). A clear dose- and concentration-dependent reduction in of ex-vivo stimulated IL-17A release was seen in volunteers treated with AZD0284, both after single and multiple dosing. No clinically significant changes in clinical laboratory assessments, vital signs or ECG were observed (Asimus et al. 2020)
Suitability
Suitable for preclinical studies
Mechanism of Action
RORγ inverse agonist
Original Therapeutic Area
Respiratory and Immunology
CNS Penetrant
Unknown
Route of administration
Oral
Modality
Small Molecule
Additional Information
1. Asimus S, Palmér R, Albayaty M, Forsman H, Lundin C, Olsson M, Pehrson R, Mo J, Russell M, Carlert S, Close D, Keeling D. Pharmacokinetics, pharmacodynamics and safety of the inverse retinoic acid-related orphan receptor γ agonist AZD0284. Br J Clin Pharmacol. 2020 Jul;86(7):1398-1405. doi: 10.1111/bcp.14253. Epub 2020 Mar 3. PMID: 32067249; PMCID: PMC7319014.