AM0902

IC50: 71 nM (rTRPA1), 131 nM (hTRPA1)

AM-0902 is a potent, selective antagonist of TRPA1 with IC ₅₀ s of 71 and 131 nM for rTRPA1 and hTRPA1, respectively. AM-0902 is highly permeable (average P _app =44.5 μcm/s in MDCK cells), an unlikely substrate for P-gp (efflux ratio=1.3 in P-gp overexpressing MDCK cells), and demonstrates good solubility (PBS pH 7.4: 226 μM, SIF: 248 μM). AM-0902 shows good selectivity over other TRP channels, as no activity is observed against human TRPV1 or TRPV4, or rat TRPV1, TRPV3, or TRPM8, at concentrations up to 10 μM. AM-0902 inhibits ⁴⁵ Ca ²⁺ flux upon activation of rat TRPA1 with methylglyoxal with an IC ₅₀ of 0.019 μM.

AM-0902 is a potent, selective antagonist of TRPA1 in vivo. AM-0902 has moderate terminal elimination half-life (t _1/2 =0.6 h and 2.8 h for rat (0.5 mg/kg, iv), rat (30 mg/kg, oral)). A dose-dependent reduction of allyl isothiocyanate (AITC)-induced flinching is observed for AM-0902, with a significant reduction in flinching observed postdosing of 10 and 30 mg/kg. The unbound plasma concentrations (C _u ) at 1 h for the 1, 3, 10, and 30 mg/kg doses are 0.051±0.024 (n=8), 0.19±0.11 (n=8), 0.58±0.35 (n=8), and 2.2±0.40 (n=8) μM, covering the in vitro rat TRPA1 ⁴⁵ Ca ²⁺ IC ₅₀ at 0.72, 2.7, 8.2, and 30.3 fold, respectively. A good exposure-response relationship is observed in this target coverage model. An unbound in vivo IC ₅₀ of 0.35 μM, which is in good agreement with the in vitro rat TRPA1 ⁴⁵ Ca ²⁺ IC ₅₀ , and unbound in vivo IC ₉₀ of 1.7 μM are determined. It is noteworthy that at a dose of 30 mg/kg, AM-0902 engages TRPA1 at concentrations that exceed the in vivo IC ₉₀ , making it a useful tool for exploration of in vivo models of acute pain.