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    • GSK has also been used as PET radiotracer

    2022-08-04

    GSK-189254 has also been used as PET radiotracer (in the form of [11C]-GSK-189254, also used as [11C]-AZ12807110 by Jucaite et al. (Jucaite et al., 2013)) to assess H3R occupancy (Ashworth et al., 2010), and is currently used in an image-based phase I clinical trial study for investigating GSK-239512 distribution in the Derquantel (NCT00474513). Efficacy of GSK-189254 in preclinical models of neuropathic pain has been reported (McGaraughty, Chu, Cowart, & Brioni, 2012; Medhurst et al., 2008). At present, a phase I trial has been completed for the safety and efficacy assessment of GSK-189254 in a electrical hyperalgesia model in healthy subjects in a double-blind, double-dummy, placebo-controlled, incomplete block, two period crossover study with no disclosure of the result (NCT00387413). GSK-239512 is another drug candidate developed by GlaxoSmithKline with chemical name 1-[6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl]-2-pyrrolidinone (Wilson et al., 2013a). From structural perspectives, it is similar to GSK-189254 but with a minor structural difference in which the carboxamide group of GSK-189254 was replaced by a pyrrolidinone ring. No violation of drug-likeness criteria has been observed for GSK-239512 (MW 377.48, MLogP 3.1, and four HBA; see Table 2). Binding assays both in vitro and in vivo revealed high affinity of GSK-239512 for rat and human H3Rs (Ashworth et al., 2014; Wilson et al., 2013a). Interestingly, the affinity was higher for human H3Rs as shown by an in vivo receptor occupancy phase I clinical trial study in healthy volunteers (NCT00474513) (Ashworth et al., 2014). In a single blind, placebo-controlled, randomized phase I trial study, the efficacy, safety, and tolerability of GSK-239512 were evaluated using a titration dose regimen in patients with mild-to-moderate Alzheimer's disease. The results of this completed clinical trial study showed that this candidate has a procognitive effect with an acceptable level of tolerability (NCT00675090) (Nathan et al., 2013). Likewise, in a completed phase II clinical trial study, a modest and selective effect of GSK-239512, alongside satisfactory safety and tolerability in patients with mild-to-moderate Alzheimer's disease have been evidenced in a randomized, double-blind, placebo-controlled study (Grove et al., 2014) (NCT01009255). Moreover, GSK-239512 has completed phase II of clinical trials for stable subjects with schizophrenia in a randomized double-blind, placebo controlled, parallel group study. Although no overall beneficial effects were achieved in cognitive impairment associated to schizophrenia (CIAS), care should be taken for the interpretation of the results since the study was performed in a small sample size and for generalizing the results a larger sample size is required (Jarskog et al., 2015) (NCT01009060). The remyelination effect of GSK-239512 in subjects with relapsing-remitting multiple sclerosis was evaluated in a randomized, parallel group, placebo-controlled, and multicenter phase II study. This phase of the study has been completed and the findings show a small positive effect on remyelination (Schwartzbach et al., 2017) (NCT01772199). A drug-drug interaction phase I trial study has been also completed for GSK-239512 in order to assess the pharmacokinetics of GSK-239512 co-administered with ketoconazole in young healthy individuals (NCT01802931). 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 compound (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).