A1480LS is a potent, in vivo active, peripherally biased and orally bioavailable dual inhibitor of DAGLα/β with IC50 of 6/4 nM (human DAGLα/β).
A1480LS potently inhibits DAGLα and DAGLβ with similar potency across species from mice, rats, dogs, monkeys, and humans with an average IC50 ≤ 15 nM.
A1480LS shows 55- and 83-fold selectivity for DAGLα and DAGLβ, respectively, over α/β hydrolase domain containing 6 (ABHD6), and greater over group VII phospholipase A2 (PLA2G7), and phospholipase DDHD2 (DDHD2).
A1480LS shows low brain penetration, inhibited both isoforms of DAGL in the kidney in rats.
A1480LS reduces pain behavior in models of inflammatory and neuropathic pain without adverse CNS effects, dose-dependently attenuates mechanical allodynia 4 h after the second dose with an ED50 of 7.7 mg/kg.
A1480LS is antinociceptive in neuropathy models and attenuates injury-induced 2-AG/AA mobilization in the sciatic nerve without enhancing PTZ-induced seizures in rats.
A1480LS suppresses mechanically evoked nociceptive input into the spinal cord dorsal horn.