AZ8838 is an effective, competitive, allosteric, orally active non-peptide small molecule antagonist of PAR2 with a pK i of 6.4 for hPAR2 [1].

AZ8838 demonstrates potent antagonistic activity by binding to an occluded pocket, significantly inhibiting SLIGRL-NH2 in Ca2+ assays with a pIC50 of 5.70 ± 0.02. It also shows a consistent potency trend in reducing IP1 production (pIC50 = 5.84 ± 0.02) and effectively attenuates peptide-induced phosphorylation of ERK1/2 (pIC50 = 5.7 ± 0.1) alongside β-arrestin-2 recruitment (pIC50 = 6.1 ± 0.1).

AZ8838 (10 mg/kg; p.o.; 2 h prior) demonstrated anti-inflammatory effects in a rat paw oedema model induced by the PAR2 agonist 2f-LIGRLO-NH2 [1]. Utilizing Wistar rats in an acute oedema model, a single oral dose was administered 2 hours before induction, resulting in a 60% reduction in paw swelling. The compound effectively inhibited the activation of mast cells induced by 2f-LIGRLO-NH2, reduced the number of tryptase-positive (AA1+ve) intact mast cells in the paw, and blocked histamine release.