ABT-639

ABT-639 is a novel, peripherally acting, selective T-type calcium channel blocker; blocks recombinant human Cav 3.2 in a voltage-dependent fashion (IC50=2 uM), attenuates LVA currents in rat DRG neurons (IC50=8 uM) ; less active at other Ca2+ channels (IC50> 30 uM) ; effectively reduces nociceptive and neuropathic pain in rats; high oral bioavailability.Pain Phase 2 Clinical (In Vivo) :ABT-639 blocks recombinant human T-type (Cav3.2) Ca2+ channels in a voltage-dependent fashion (IC50=2 μM) and attenuates low voltage-activated (LVA) currents in rat DRG neurons (IC50=8 μM) . ABT-639 is significantly less active at other Ca2+ channels (e.g. Cav1.2 and Cav2.2) (IC50>30 mM) . ABT-639 has high oral bioavailability (%F=73), low protein binding (88.9%) and a low brain:plasma ratio (0.05:1) in rodents. Following oral administration ABT-639 produces dose-dependent antinociception in a rat model of knee joint pain (ED50=2 mg/kg, p.o.) . ABT-639 (10-100 mg/kg, p.o.) also increases tactile allodynia thresholds in multiple models of neuropathic pain (e.g. spinal nerve ligation, CCI, and vincristine-induced, and capsaicin secondary hypersensitivity) . ABT-639 does not attenuate hyperalgesia in inflammatory pain models induced by complete Freund’s adjuvant or carrageenan. At higher doses (e.g. 100-300 mg/kg) ABT-639 does not significantly alter hemodynamic or psychomotor function. The antinociceptive profile of ABT-639 provides novel insights into the role of peripheral T-type (Cav3.2) channels in chronic pain states.