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  • Dual H H receptor antagonists developed by GlaxoSmithKline

    2021-09-18

    Dual H1/H3 receptor antagonists developed by GlaxoSmithKline have also reached clinical trials at various stages. These candidates are useful for alleviating the symptoms associated with allergic rhinitis(Daley-Yates et al., 2012). GSK-1004723, 4-[(4-chlorophenyl)methyl]-2-( (2R)-1-[4-(4- [3-(hexahydro-1H-azepin-1-yl)propyl]oxy phenyl)butyl]-2-pyrrolidinyl methyl)-1(2H)-phthalazinone, is one of these H1/H3 receptor antagonists with high affinity for recombinant H1 and H3 receptors as shown by radioligand binding assays (Slack et al., 2011). In spite of its antagonistic effect on H3Rs, no drug-likeness properties were observed for this Palifosfamide (Table 2). Additionally, it had prolonged duration of activity at H1 and H3 receptors, possibly due to its lipophilic and dibasic nature as well as slow dissociation rate in the vicinity of receptors, leading to daily single dose administration of the compound (Slack et al., 2011). GSK-1004723 is formulated as suspension or solution for intranasal administration; however, single-dose intranasal administration is not significantly efficient to reduce symptoms associated with allergic rhinitis compared to cetirizine. Allergic rhinitis symptoms were reduced following intranasal administration in the form of a three-day repeated dose (Daley-Yates et al., 2012). Currently, three clinical trial studies are conducted for efficacy, safety, pharmacokinetic, and tolerability evaluation of GSK-1004723 in healthy subjects and patients with seasonal allergic rhinitis (NCT00824356; NCT00972504; NCT00694993). GSK-835726 (3-[4-[4-[4-[4-(3,3-dimethylpiperidin-1-yl)butoxy]phenyl]piperidine-1-carbonyl]naphthalen-1-yl]propanoic acid) is a dual H1/H3 receptor antagonist with the potential to be used in allergic rhinitis. Likewise GSK-1004723, the drug-likeness criteria have not been passed by this drug candidate; nonetheless, it is a well-tolerated, highly bioavailable and long acting agent. The antagonistic effect of GSK-835726 at H1 and H3 receptors has been reported for in vivo animal models. Three completed clinical trial studies (i.e. phases I and II) are in progress for evaluating efficacy, safety, and tolerability of GSK-835726 in healthy individuals and subjects with seasonal allergic rhinitis (NCT00851344; NCT00605852; and NCT00972504). These studies showed that the efficacy profile of GSK-835726 in allergic rhinitis is comparable with cetirizine with once-daily oral administration (Daley-Yates et al., 2012). Another H3R antagonist developed by GlaxoSmithKline is GW784568X (1- 4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl]-4- [4-(methylsulfonyl)phenyl]carbonyl piperazine). This drug candidate contains all the drug-likeness properties except Ghose parameters (Table 2). The MW, HBA, and MLogP of GW784568X are 497.65, 5, and 2.83, respectively. No comprehensive information is available in the public domain; however, some studies show that this candidate is highly selective towards H3Rs with good CNS penetration in animal models (Norman, 2007). In 2010, Johnson & Johnson synthesized and identified a series of compounds with an aryloxypyridine amide scaffold as H3R antagonists (Letavic et al., 2010). Among the synthesized compounds, JNJ-39220675 ((4-cyclobutyl-1,4-diazepan-1-yl)-[6-(4-fluorophenoxy)pyridin-3-yl]methanone) exhibited high affinity for H3Rs receptors and enhanced histamine levels in rat frontal cortex and showed wake-promoting ability in preclinical studies (Letavic et al., 2010). Different synthesis routes for scaling up have been proposed for this compound (Pippel et al., 2011). This drug candidate with MW 369.43, five HBA, and MLogP 3.04 possesses all the drug-likeness criteria (Table 2). Preclinical PET studies using [11C]-GSK-189254 in baboons showed that JNJ-39220675 has a receptor occupancy at H3Rs > 90% following oral and intravenous administration (Logan et al., 2012). JNJ-39220675 has completed a phase II clinical trial study in patients with allergic rhinitis in a randomized, single-dose, single-blind, double-dummy, placebo-controlled, and three-way cross-over study that compared its effectiveness with pseudoephedrine (NCT00804687), and showed that JNJ-39220675 alleviated the symptoms of allergen-induced nasal congestion (Barchuk, Salapatek, Ge, D'Angelo, & Liu, 2013). Additionally, several preclinical studies reveal that JNJ-39220675 has the potential to reduce alcohol abuse-related behaviors in rat models of alcoholism (Galici et al., 2011). Since alcoholism and drug abuse are often observed in cognitive disorders, H3R antagonists could have beneficial effects on alcohol dependency (Galici et al., 2011; Nuutinen et al., 2012; Nuutinen et al., 2016). However, further experiments are required to verify the pharmacotherapeutic efficacy of H3R antagonists, including JNJ-39220675, in alcohol addiction to allow their evaluation in clinical trials in the near future.