Pharmacological characterization of a novel potent, selective, and orally active orexin 2 receptor antagonist, SDM‐878

Abstract

Aims Recently, we identified a novel orexin 2 (OX 2 ) receptor antagonist, SDM‐878 (2‐(3‐(2‐(1 H ‐pyrazol‐1‐yl)nicotinoyl)‐3,8‐diazabicyclo[3.2.1]octan‐8‐yl)‐3‐methoxyisonicotinonitrile). The purpose of the present study is to characterize the in vitro and in vivo pharmacological effects of SDM‐878. Methods The in vitro potency and selectivity of SDM‐878 were examined in CHO cells that exhibit stable expression of human orexin 1 (OX 1 ), human orexin 2 (OX 2 ), rat OX 1 , and rat OX 2 receptors. Then, the plasma half‐life, oral bioavailability, and brain penetration of SDM‐878 were examined in rats. The in vivo effect of SDM‐878 in rats was tested using electroencephalography (EEG). The target engagement of SDM‐878 in the rat brain was examined using the antagonistic effect against hyperlocomotion caused by the intracerebroventricular administration of the OX 2 receptor agonist, ADL‐OXB ([Ala 11 , d‐Leu 15 ]‐orexin B). Results SDM‐878 showed potent inhibitory activities for human and rat OX 2 receptors with IC values of 10.6 and 8.8 nM, respectively, and approximately 1000‐fold selectivity against the OX 1 receptor. In rat studies, SDM‐878 exhibited a relatively short half‐life in plasma, oral bioavailability, and good brain penetration. These data indicate that SDM‐878 is a potent, selective, orally active, and brain‐penetrable OX 2 receptor antagonist. In behavioral studies using rats, SDM‐878 (100 mg/kg) antagonized hyperlocomotion caused by intracerebroventricular administration of ADL‐OXB. SDM‐878 exhibited a potent sleep‐promoting effect at the same dose (100 mg/kg) in a rat EEG study. Conclusion Our results suggest that SDM‐878 is likely to be a good pharmacological tool for investigating the role of the OX 2 receptor and may have therapeutic potential for the treatment of insomnia.

Pyrazole derivatives as selective orexin-2 receptor antagonists (2-SORA): synthesis, structure–activity–relationship, and sleep-promoting properties in rats

“…Methylation of the N-indole (42) decreased the compound's potency on both OXRs. Compared to indole 41, 4-azaindole (43) was less potent on OX 2 R, resulting in a less selective compound towards OX 2 R. The intrinsic clearance for 41 and 43, in HLM was 46 and 92 μL min −1 mg −1 , respectively. While the 3-linked indoles 41 and 43 showed lower shifts in the TDI of CYP3A4 than their N-linked analogs 33 and 38, respectively, IC 50 -values for CYP3A4 inhibition still markedly decreased with prolonged incubation time.…”

“…42 Other recently introduced 2-SORA compounds include SDM-878 16 (ref. 43) and JNJ-48816274. 44 The structure of the latter compound has not been disclosed.…”

Current status, mechanism and research progress of major sedative-hypnotic drugs for the treatment of insomnia

“…Over the past 20 years, dozens of compounds have been developed by national and international pharmaceutical companies targeting the orexin receptor, including selective orexin receptor-1 antagonists (1-SORAs), selective orexin receptor-2 antagonists (2-SORAs), and dual orexin receptor antagonists (DORAs). Among them, 1-SORAs have no sig-nificant improvement in insomnia, 27 some 2-SORAs only show potent hypnotic effects in animal studies, and further clinical studies are still needed, 28 and DORAs, because of their significant hypnotic effects and good safety, have become the main research and development direction for the treatment of insomnia with orexin receptor antagonists. Currently, there are three dual orexin receptor antagonists approved by the U.S. Food and Drug Administration (FDA) for the treatment of insomnia, namely Suvorexant, Lemborexant and Daridorexant.…”

Targeting Orexin Receptors for the Treatment of Insomnia: From Physiological Mechanisms to Current Clinical Evidence and Recommendations

“… 47 Other OX2R-selective SORAs have been subjected to preclinical development. 214 , 219 , 220 Recently, OX1R-selective SORAs 221–225 have been developed, but their effects on sleep are minor 225 or still unclear. 221–224 …”