AZ11657312
Preclinical pharmacology
AZ11657312 is a potent antagonist of the rat P2X7 receptor with a pA2 for inhibition of agonist-stimulated ethidium bromide release of 7.8 (15nM) in HEK cells expressing the recombinant rat P2X7 receptor. Treatment of rats with AZ11657312 at 30-60mg/kg BID orally (plasma compound levels of at least 3 x pA2) resulted in a significant reduction in mechanical hyperalgesia and disease severity in the streptococcal cell wall model of arthritis, and a delay in the adjuvant-induced arthritis model.
Potency of AZ11657312 is ~50x lower at the human P2X7 receptor [pA2 of 6.1 (794nM)], so in vitro studies using human cells or tissues would require higher concentrations.
Suitable for and exclusions
AZ11657312 is suitable for preclinical experiments only and, at this time, there is no clinically enabled molecule available for translation to clinical studies.
Mechanism of Action
Purinergic receptor 2X, ligand-gated ion channel 7 (P2X7) antagonist
Original Therapeutic Area
Other
CNS Penetrant
Low
Route of administration
Oral
Modality
Small Molecule
Additional Information
1. Broom DC., et al. (2008).
Cortright Journal of Pharmacology and Experimental Therapeutics December 2008, 327 (3) 620-633; DOI: 10.1124/jpet.108.141853.
