PF-06372865

1614245-70-3

440.49

DMSO : 100 mg/mL (ultrasonic)

Neuronal Signaling; Membrane Transporter/Ion Channel

PF-06372865 is an orally active, alpha2/alpha3/alpha5 subtype-selective GABAA positive allosteric modulator (PAM). PF-06372865 is a high affinity ligand at GABAA receptors containing alpha1/alpha2/alpha3/alpha5 subunits (Kis of 2.9 nM, 21 nM, 134 nM for alpha2, alpha1 PAM, alpha2 PAM, respectively), with low affinity for alpha4/alpha6 subunits. PF-06372865 can across the blood-brain barrier (BBB). PF-06372865 has anxiolytic activity and has the potential for epilepsy.
IC50 & Target: Ki: 2.9 nM (alpha2), 21 nM (alpha1 PAM) and 134 nM (alpha2 PAM)
In Vitro: PF-06372865 (compound 34) has Ki values of 0.18 nM, 2.9 nM, 1.1 nM, 18 nM for human GABAA alpha1beta3gamma2, alpha2beta2gamma2, alpha3beta3gamma2, alpha5beta2gamma2 and 0.34 nM, 4.58 nM for rat GABAA alpha1beta3gamma2, alpha2beta2gamma2.

In Vivo: PF-06372865 (compound 34; 3, 10 mg/kg; orally; single dose) significantly increases the paw withdrawal threshold (PWT) in chronic constriction injury (CCI) animals.

PF-06372865 (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).

PF-06372865 (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).

PF-06372865 has a T1/2 of 1.1 hours, a Clp of 22 mL/min/kg, and a Vss of 2.1 L/kg for rats.

PF-06372865 has a T1/2 of 0.9 hours, a Clp of 29 mL/min/kg, and a Vss of 3.4 L/kg for dogs.