SB-674042

Description: SB-674042 is a novel, potent and selective non-peptide orexin OX1 receptor antagonist with Kd of 3.76 nM; It exhibits 100-fold selectivity for OX1 over OX2 receptors. The orexins and their receptors are involved in the regulation of arousal and sleep-wake cycle. Clinical investigation with almorexant has indicated that this dual OX antagonist is efficacious in inducing and maintaining sleep.Despite high similarities in the ligand-binding pockets of OX(1) and OX(2) and numerous aromatic/hydrophobic interactions, the local conformation of helix positions 3.32, 3.33, and 3.36 in transmembrane domain 3 and 45.51 in ECL2b provide the structural basis for pharmacologic selectivity between OX(1) and OX(2).

References: Mol Pharmacol. 2010 Jul; 78(1):81-93.