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  • Betahistine N methyl pyridyl ethylamine

    2022-09-08

    Betahistine (N-methyl-2-(2-pyridyl)ethylamine) is a well-known dual H1 leukotriene receptor antagonist agonist/H3 receptor antagonist with structural resemblance to histamine. Though it has been approved long before the discovery of H3R to treat disorders of vestibular function as Menières-Disease, the evidence for this indication is not clear until today (Casani, Navari, Guidetti, & Lacour, 2018). Recently, a meta-analysis by the Cochrane collaboration including studies from 1967 to 2012 assessed the benefit of betahistine in treatment of patients suffering from idiopathic and secondary vertigo. Among 11 studies including 606 patients in total, the reduction of symptoms was higher in the group receiving betahistine than placebo while not showing more adverse events (Murdin, Hussain, & Schilder, 2016). Despite low evidence due to high statistical heterogeneity of the studies, betahistine remains an attractive agent still being evaluated in several studies. Among them, a phase I study (program AM-125) from Auris Medical has been completed using the drug in a formulation for intranasal application resulting in significant increase of bioavailability, presumably enhancing effectiveness (AG, 2018) CEP-26401, known as Irdabisant (6- 4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl -2H-pyridazin-3-one]), is another H3R antagonist/inverse agonist (MW 313.39). CEP-26401 was first reported by Hudkins et al., 2011 (Hudkins et al., 2011), and is under development by Teva Pharmaceutical Industries. This candidate has excellent physicochemical properties that make it ideal from a drug-likeness (Table 2) and pharmacokinetic perspective (Hudkins, Raddatz, et al., 2011). The antagonistic effect of CEP-26401 in rat and human H3R expressing systems was investigated with results indicative of high affinity in radioligand binding assays (Raddatz et al., 2012).The pharmacokinetic, pharmacodynamic, and safety of CEP-26401 were evaluated in two randomized, double-blind, placebo-controlled studies in healthy subjects. The findings showed that this drug candidate has dose- and time-independent pharmacokinetics, being well tolerated after single and multiple oral administrations with a major elimination pathway via renal excretion (Spiegelstein et al., 2016). A phase I clinical trial has been completed for assessing CEP-26401 in cognitive impairment in healthy individuals without disclosing any results (NCT01903824). Although CEP-26401 is under clinical trial study, several projects are in progress for synthesizing novel irdabisant analogs in order to improve the pharmacokinetic and pharmacodynamic profile (Hudkins, Aimone, et al., 2011; Hudkins et al., 2015; Josef, Aimone, Lyons, Raddatz, & Hudkins, 2012). GSK-189254, 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide, is a benzazepine-based H3R antagonist/inverse agonist under development by GlaxoSmithKline. It was introduced as one of the potential H3R antagonists among different synthetic benzazepine derivatives (Wilson et al., 2013a; Wilson et al., 2013b). GSK-189254 has MW 351.44 g/mol, MLogP 2.67, and HBA and HBD numbers of four and one, respectively. This candidate possesses all the drug-likeness criteria listed in Table 2, and high affinity and selectivity towards the H3R as evidenced by radioligand binding studies with recombinant and native H3Rs of several species. GSK189254 elevated acetylcholine, noradrenaline, and dopamine levels in the anterior cingulate cortex as well as acetylcholine levels in the dorsal hippocampus, presumably by blocking H3 heteroreceptors (Medhurst et al., 2007). In addition, the effect of GSK-189254 on histaminergic neurons was investigated in rats and the findings showed region-specific differences in the release of histamine and other neurotransmitters, attributable to distinct histaminergic pathways. This study also showed that GSK-189254 reversed the amnesic effect of scopolamine using object recognition test in rats (Giannoni et al., 2010).