SB-649868

A potent, selective, orally bioavailable, dual orexin OX1/OX2R antagonist with pKi of 9.4 and 9.5 respectively; displays >1,000-fold selectivity for the orexin target receptors in a broad panel of GPCRs, ion channels and enzymes; demonstrates high effectivity in pre-clinical model of sleep disorders.Sleep Disorder Phase 2 Discontinued (In Vitro) :SB-649868 is identified as one the most in vitro potent dual OX1 and OX2 receptor antagonist known at that time (pKi=9.4 and 9.5 at the OX1 and OX2 receptor, respectively) . SB-649868 antagonizes orexin-A-induced inositol 1 phosphate (IP1) accumulation with the following pKB value (OX1=9.67; OX2=9.64) . SB-649868 displaces the [3H]ACT-078573 receptor binding with the following pKi values: OX1=9.27; OX2=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 pKb values are 9.67±0.03 and 9.64±0.07 for OX1 and OX2.