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  • A phase I clinical trial has been completed for assessing

    2021-10-12

    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 VLX600 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). 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 brain (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).