Usmarapride (SUVN-D4010), a 5-HT4 receptor partial agonist for the potential treatment of Alzheimer's disease: Behavioural, neurochemical and pharmacological profiling.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder which affects cognitive functions with negative impact on day to day activities and an ultimate loss of independent living. Current standard of care (SOC) for AD, viz. donepezil, rivastigmine, galantamine, memantine etc. either alone or in combination show modest efficacy without changing the course of the disease. On prolonged treatment, side effects are more common with an eventual loss of efficacy. Aducanumab, a monoclonal antibody is a disease modifying therapeutic agent targeting the toxic amyloid beta (Aß) proteins for its clearance. However, it is found to have only modest efficacy in AD patients and its approval by FDA is controversial. Alternate, effective and safe therapeutics are need of the hour, as AD cases are expected to be doubled by 2050. Recently, 5-HT4 receptors have been envisioned as target for alleviating AD associated cognitive impairment with potential disease modifying ability impacting disease progression. Usmarapride is a 5-HT4 receptor partial agonist, being developed for the possible treatment of AD with symptomatic and disease modifying potential. Usmarapride demonstrated promising effects in ameliorating cognitive deficits in diverse animal models of episodic, working, social, and emotional memories. Usmarapride produced elevation in cortical acetylcholine levels in rats. Furthermore, usmarapride increased levels of soluble amyloid precursor protein alpha, a potential mechanism to reverse toxic Aß peptide pathology. Usmarapride also potentiated the pharmacological effects of donepezil in animal models. To conclude, usmarapride may be a promising intervention for alleviating the cognitive dysfunction in AD patients with disease modifying potential.

Ropanicant (SUVN-911), an α4ß2 nicotinic acetylcholine receptor antagonist intended for the treatment of depressive disorders: pharmacological, behavioral, and neurochemical characterization.

RATIONALE: Ropanicant (SUVN-911) (3-(6-Chloropyridine-3-yloxymethyl)-2-azabicyclo (3.1.0) hexane hydrochloride) is a novel α4ß2 nicotinic acetylcholine receptor (nAChR) antagonist being developed for the treatment of depressive disorders. OBJECTIVES: Pharmacological and neurochemical characterization of Ropanicant to support a potential molecule for the treatment of depressive disorders. METHODS: Ropanicant was assessed for antidepressant-like activity using the rat forced swimming test (FST) and differential reinforcement of low rate -72 s (DRL-72 s). Alleviation of anhedonia was assessed in chronic mild stress model using sucrose preference test. To understand the mechanism of action, serotonin levels, ionized calcium-binding adaptor molecule 1 (Iba1), and brain-derived neurotrophic factor (BDNF) were determined. The onset of antidepressant-like activity was determined using the reduction in submissive behavior assay. The effects on cognition and sexual functions were assessed using the object recognition task and sexual dysfunction assay respectively. Interaction of Ropanicant, TC-5214, and methyllycaconitine (MLA) with citalopram was investigated individually in mice FST. RESULTS: Ropanicant exhibited antidepressant like properties in the FST and DRL-72 s. A significant reduction in anhedonia was observed in the sucrose preference test. Oral administration of Ropanicant produced a significant increase in serotonin and BDNF levels, with a reduction in the Iba1 activity. The onset of antidepressant like effect with Ropanicant was within a week of treatment, and was devoid of cognitive dulling and sexual dysfunction. While Ropanicant potentiated the effect of citalopram in FST, such an effect was not observed with MLA or TC-5214. CONCLUSIONS: Preclinical studies with Ropanicant support the likelihood of its therapeutic utility in the treatment of depressive disorders.

Discovery and Preclinical Characterization of Usmarapride (SUVN-D4010): A Potent, Selective 5-HT4 Receptor Partial Agonist for the Treatment of Cognitive Deficits Associated with Alzheimer's Disease.

A series of oxadiazole derivatives were synthesized and evaluated as 5-hydroxytryptamine-4 receptor (5-HT4R) partial agonists for the treatment of cognitive deficits associated with Alzheimer's disease. Starting from a reported 5-HT4R antagonist, a systematic structure-activity relationship was conducted, which led to the discovery of potent and selective 5-HT4R partial agonist 1-isopropyl-3-{5-[1-(3-methoxypropyl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate (Usmarapride, 12l). It showed balanced physicochemical-pharmacokinetic properties with robust nonclinical efficacy in cognition models. It also showed disease-modifying potential, as it increased neuroprotective soluble amyloid precursor protein alpha levels, and dose-dependent target engagement and correlation of efficacy with oral exposures. Phase 1 clinical studies have been completed and projected efficacious concentration was achieved without any major safety concerns. Phase 2 enabling long-term safety studies have been completed with no concerns for further development.

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

BACKGROUND: Central histamine H3 receptors are a family of presynaptic auto and heteroreceptors. Blockade of the presynaptic H3 receptors activates the downstream pathway(s) involved in the processes of learning and memory, making it a potential therapeutic option for ameliorating cognitive dysfunction. Samelisant (SUVN-G3031) is a potent and selective inverse agonist at the H3 receptors. AIM: The aim of this research is to study the effects of Samelisant in diverse animal models of cognitive functions. METHODS: The effects of Samelisant on cognitive functions were studied using social recognition, object recognition and Morris water maze tasks. Neurochemical and electrophysiological effects of Samelisant were monitored using microdialysis and electroencephalography techniques. RESULTS: Samelisant showed procognitive effects in diverse animal models of cognition at doses ranging from 0.3 to 3 mg/kg, per os (p.o.) (social recognition and object recognition task). Samelisant significantly increased the brain acetylcholine levels in the cortex at doses of 10 and 20 mg/kg, p.o. In the Morris water maze task, combined administration of suboptimal doses of Samelisant and donepezil resulted in procognitive effects significantly larger than the either treatment. Similarly, Samelisant significantly potentiated the effects of donepezil on pharmacodynamic biomarkers of cognition i.e. acetylcholine levels in brain and neuronal theta oscillations. CONCLUSION: Samelisant may have potential utility in the treatment of cognitive deficits associated with hypocholinergic state.

Samelisant (SUVN-G3031), a potent, selective and orally active histamine H3 receptor inverse agonist for the potential treatment of narcolepsy: pharmacological and neurochemical characterisation.

RATIONALE: Samelisant (SUVN-G3031) is a potent and selective histamine H3 receptor (H3R) inverse agonist with good brain penetration and oral bioavailability. OBJECTIVES: Pharmacological and neurochemical characterisation to support the utility of Samelisant (SUVN-G3031) in the treatment of sleep-related disorders like narcolepsy. METHODS: Samelisant (SUVN-G3031) was tested in rat brain microdialysis studies for evaluation of modulation in histamine, dopamine and norepinephrine. Sleep EEG studies were carried out in orexin knockout mice to study the effects of Samelisant (SUVN-G3031) on the sleep-wake cycle and cataplexy. RESULTS: Samelisant (SUVN-G3031) has a similar binding affinity towards human (hH3R; Ki = 8.7 nM) and rat (rH3R; Ki = 9.8 nM) H3R indicating no inter-species differences. Samelisant (SUVN-G3031) displays inverse agonist activity and it exhibits very high selectivity towards H3R. Samelisant (SUVN-G3031) treatment in mice produced a dose-dependent increase in tele-methylhistamine levels indicating the activation of histaminergic neurotransmission. Apart from increasing the levels of histamine, Samelisant (SUVN-G3031) also modulates dopamine and norepinephrine levels in the cerebral cortex while it has no effects on dopamine levels in the striatum or nucleus accumbens. Treatment with Samelisant (SUVN-G3031; 10 and 30 mg/kg, p.o.) produced a significant increase in wakefulness with a concomitant decrease in NREM sleep in orexin knockout mice subjected to sleep EEG. Samelisant (SUVN-G3031) also produced a significant decrease in Direct REM sleep onset (DREM) episodes, demonstrating its anticataplectic effects in an animal model relevant to narcolepsy. Modulation in cortical levels of histamine, norepinephrine and dopamine provides the neurochemical basis for wake-promoting and anticataplectic effects observed in orexin knockout mice. CONCLUSIONS: Pre-clinical studies of Samelisant (SUVN-G3031) provide a strong support for utility in the treatment of sleep-related disorders related to EDS and is currently being evaluated in a phase 2 proof of concept study in the USA for the treatment of narcolepsy with and without cataplexy.