pKi: 9.4 (OX ₁ ), 9.5 (OX ₂ )

SB-649868 is identified as one the most in vitro potent dual OX ₁ and OX ₂ receptor antagonist known at that time (pK _i =9.4 and 9.5 at the OX ₁ and OX ₂ receptor, respectively) . SB-649868 antagonizes orexin-A-induced inositol 1 phosphate (IP1) accumulation with the following pK _B value (OX ₁ =9.67; OX ₂ =9.64). SB-649868 displaces the [ ³ H]ACT-078573 receptor binding with the following pKi values: OX ₁ =9.27; OX ₂ =8.91. Increasing concentrations of SB-649868 (0.3 nM-30 nM) induces a rightward shift of the orexin-A CRCs with a depression of the agonist efficacy suggesting a clear non-surmountable behavior. The calculated apparent pK _b values are 9.67±0.03 and 9.64±0.07 for OX ₁ and OX ₂ .

Pharmacokinetic studies in the male CD rat, performed at 1 mg/kg, iv and 3 mg/kg, po, demonstrate an excellent pharmacokinetic profile for a hypnotic agent featuring moderate clearance in plasma (Cl _p =24 mL/min/kg), short half-life of (<0.6 h) and a low volume of distribution (V _ss =1.1 l/kg), coupled with excellent oral bioavailability (F=85%) and good exposure in plasma (C _max =333 ng/mL). A brain to blood ratio (B/B) of 0.1:1 is observed 1 h after iv administration, a value in line with the expected partition between the two compartments based on the lower tissue binding observed in vitro in brain tissues (fraction unbound/brain=5.28%) with respect to plasma proteins (fraction unbound/plasma=1.34%). SB-649868, administered orally 3 h before OX-A injection at doses of 1, 3 and 10 mg/kg, causes a dose-dependent reduction of OX-A induced grooming as measured by total time spent grooming and number of grooming bouts (p <0.01 at 3 and 10 mg/kg po) . From dissociation kinetic studies using [ ³ H]ACT-078573, the calculated long half-life, (t _1/2 ) supports the non-surmountability profile of SB-649868 (t _1/2 =35.91 min) at OX ₁ orexin receptor. The long or moderately long t _1/2 values for SB-649868 at OX ₂ orexin receptor (t _1/2 =8.09 min).