Discovery process and pharmacological characterization of a novel dual orexin 1 and orexin 2 receptor antagonist useful for treatment of sleep disorders

Role of Orexin-1 Receptor Mechanisms on Compulsive Food Consumption in a Model of Binge Eating in Female Rats

“…On the contrary, the OX 1 R antagonist GSK1059865 showed a very poor hypnotic ability to induce and maintain sleep. These findings are in keeping with other reports suggesting that OX 2 R might be more important than OX 1 R in mediating the OX effect on sleep (Sakurai, 2007;Brisbare-Roch et al, 2007;Malherbe et al, 2009;Dugovic et al, 2009;Di Fabio et al, 2011).…”

“…Finally, the compounds were tested at the defined doses in the BE model. OX 1 R and OX 2 R antagonists are reported in the literature to be involved in the control of sleep, in particular to induce hypnotic effects (Di Fabio et al, 2011;Gozzi et al, 2011;Dugovic et al, 2009). In a preclinical hypnotic sleep model in male rats, the results obtained demonstrated that the dual OX 1 /OX 2 R antagonist, SB-649868, induced a robust hypnotic effect, both on the ability to induce and to maintain sleep, reaching a statistically significant effect at 3 mg/kg.…”

“…Moreover, the simultaneous antagonism of both OX 1 R and OX 2 R or the selective inhibition of OX 2 R results in the induction of a strong hypnotic effect (Brisbare-Roch et al, 2007;Dugovic et al, 2009;Di Fabio et al, 2011).…”

“…Therefore, this study was aimed at investigating the effect of the dual OX 1 /OX 2 R antagonist SB-649868 (N-[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]-1-benzofuran-4-carboxamide) (Di Fabio et al, 2011), the selective OX 1 R antagonist GSK1059865 (5-bromo-N-[(2S,5S)-1-(3-fluoro-2-methoxybenzoyl)-5-methylpiperidin-2-yl]methyl-pyridin-2-amine) (Gozzi et al, 2011), and the selective OX 2 R antagonist JNJ-10397049 (N-(2,4-dibromophenyl) (McAtee et al, 2004;Dugovic et al, 2009) in the BE model described by Cifani et al (2009), in which BE episodes for HPF is evoked in female rats by cycles of food restriction/re-feeding and acute stress. The three antagonists were first evaluated in vitro in rat recombinant OX 1 R and OX 2 R to determine their potency and to confirm their selectivity for the two receptor subtypes.…”

International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology

“…SB-649868 was reported to inhibit both OX 1 and OX 2 receptor activity and entered clinical trials in 2005. Preclinically, SB-649868 was shown to be sleeppromoting in rodent and primate studies (Di Fabio et al, 2011). In 2007, GSK announced that SB-649868 had advanced to phase II clinical trials.…”