Darigabat

Darigabat (PF-06372865) is an orally active, α2/α3/α5 subtype-selective GABA_A positive allosteric modulator (PAM). Darigabat is a high affinity ligand at GABA_A receptors containing α1/α2/α3/α5 subunits (K_is of 2.9 nM, 21 nM, 134 nM for α2, α1 PAM, α2 PAM, respectively), with low affinity for α4/α6 subunits. Darigabat can across the blood-brain barrier (BBB). Darigabat has anxiolytic activity and has the potential for epilepsy^[1]. IC50 & Target:Ki: 2.9 nM (α2), 21 nM (α1 PAM) and 134 nM (α2 PAM)^[1] In Vitro:Darigabat (compound 34) has K_i values of 0.18 nM, 2.9 nM, 1.1 nM, 18 nM for human GABA_A α1β3γ2, α2β2γ2, α3β3γ2, α5β2γ2 and 0.34 nM, 4.58 nM for rat GABA_A α1β3γ2, α2β2γ2^[1].
In Vivo:Darigabat (compound 34; 3, 10 mg/kg; orally; single dose) significantly increases the paw withdrawal threshold (PWT) in chronic constriction injury (CCI) animals^[1].
Darigabat (0.3, 3, 10 mg/kg for mouse and 1, 3, 10 mg/kg for rat; orally) exhibits efficacy in two models of epilepsy, PTZ induced seizures (mouse), and amygdala kindling (rat)^[1].
Darigabat (0.1, 0.32, 1, 3.2 and 10 mg/kg; orally) has anxiolytic activity at 3.2 and 10 mg/kg in elevated plus maze (male C57Bl/6 mice)^[1].
Darigabat has a T_1/2 of 1.1 hours, a Cl_p of 22 mL/min/kg, and a V_ss of 2.1 L/kg for rats^[1].
Darigabat has a T_1/2 of 0.9 hours, a Cl_p of 29 mL/min/kg, and a V_ss of 3.4 L/kg for dogs^[1].