Discovery and Development of N-[4-(1-Cyclobutylpiperidin-4-yloxy)phenyl]-2-(morpholin-4-yl)acetamide Dihydrochloride (SUVN-G3031): A Novel, Potent, Selective, and Orally Active Histamine H₃ Receptor Inverse Agonist with Robust Wake-Promoting Activity

Abstract

A series of chemical optimizations guided by in vitro affinity at a histamine H3 receptor (H3R), physicochemical properties, and pharmacokinetics in rats resulted in identification of N-[4-(1-cyclobutyl-piperidin-4-yloxy)­phenyl]-2-(morpholin-4-yl)­acetamide dihydrochloride (17v, SUVN-G3031) as a clinical candidate. Compound 17v is a potent (hH3R K i = 8.73 nM) inverse agonist at H3R with selectivity over other 70 targets, Compound 17v has adequate oral exposures and favorable elimination half-lives both in rats and dogs. It demonstrated high receptor occupancy and marked wake-promoting effects with decreased rapid-eye-movement sleep in orexin-B saporin lesioned rats supporting its potential therapeutic utility in treating human sleep disorders. It had no effect on the locomotor activity at doses several fold higher than its efficacious dose. It is devoid of hERG and phospholipidosis issues. Phase-1 evaluation for safety, tolerability, and pharmacokinetics, and long-term safety studies in animals have been successfully completed without any concern for further development.

Histamine 3 receptor inverse agonist Samelisant (SUVN-G3031): Pharmacological characterization of an investigational agent for the treatment of cognitive disorders

“…Samelisant had the highest receptor occupancy (90% at 3 mg/kg, p.o .) at 1 h post-treatment (Nirogi et al, 2019b). Hence, the experiments were designed to comprehend the effects of Samelisant at 1 h post-treatment after oral administration.…”

“…Samelisant is a novel and selective inverse agonist at H3 receptors with a Ki of 8.73 nM and 9.8 nM at human and rat receptors, respectively (Nirogi et al, 2019b). It has adequate oral exposures and brain penetration in rats.…”

“…Based on the information available until now, Samelisant shows selectivity towards a panel of 70 targets (Nirogi et al, 2019b) and has no safety concerns when evaluated in healthy humans (Nirogi et al, 2020). The receptor occupancy profile in rats suggests approximately 50% H3 receptor occupancy at 8 h post-treatment.…”

Saporin from Saponaria officinalis as a Tool for Experimental Research, Modeling, and Therapy in Neuroscience

“…Most importantly, recent studies used the aforementioned models of narcolepsy-like behavior, which are induced by orexin-saporin injections in the hypothalamus, to find possible drug treatments for sleeping disorders in humans. Cannabidiol, a phytocannabinoid which lacks strong psychic effects, was found to decrease sleepiness [56] as well as inverse agonist of histamine H3 receptors appeared to have pronounced wake-promoting effect [57] in the saporin-based model of narcolepsylike behavior. An important aspect of sleep research is related to analysis of adenosine accumulation in the basal forebrain, which is thought to be one of important regulators of sleep.…”

Effects of N-Substituents on the Functional Activities of Naltrindole Derivatives for the δ Opioid Receptor: Synthesis and Evaluation of Sulfonamide Derivatives

“…Neutral antagonists themselves do not exhibit any activities and can block the functions of both agonists and inverse agonists. Recently, the relationship between some disease states and the constitutive activity of receptors, and developments of inverse agonists have been reported [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. In the opioid field, since Costa and Herz firstly reported that peptidic ICI-174,864 showed δ opioid receptor (DOR) inverse agonist activity [ 21 ], several peptidic and non-peptidic DOR inverse agonists have been developed [ 4 ].…”