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  • GSK dimethylpiperidin yl butoxy phenyl piperidine carbonyl

    2022-09-29

    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 BS-181 HCl (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. A second H3R antagonist with benzamide-based structure from Johnson & Johnson is JNJ-31001074, known as Bavisant and under chemical IUPAC name of (4-cyclopropylpiperazin-1-yl)-[4-(morpholin-4-ylmethyl)phenyl]methanone. It is a compound with molecular weight 329.44, HBA four, and MLogP 1.52 encompassing all the properties required for drug-likeness criteria. A preclinical study of JNJ-31001074 revealed that this drug candidate has high affinity towards H3Rs and increases acetylcholine levels in rat frontal cortex. Recent research revealed a H3R occupancy about 90% after per oral administration decreasing to approx. 40% after 7h (Troxler et al., 2019). The pharmacokinetic profile of this candidate is satisfying in terms of plasma concentration, receptor occupancy, and safety (Letavic et al., 2015). There are eight ongoing clinical trial studies for JNJ-31001074 at different stages. JNJ-31001074 has completed phases for ADHD in pediatric and adult populations. In pediatric subjects, the pharmacokinetics, safety, and tolerability of JNJ-31001074 was evaluated in an open-label, multi-center, sequential group, ascending dose study (NCT00890240 and NCT00890292), whereas the safety and efficacy of JNJ-31001074 in adult patients was assessed using a multi-center, double-blind, placebo-controlled, randomized, and parallel-group study (NCT00566449 and NCT00880217). Although no significant effectiveness of JNJ-31001074 has been achieved in clinical trials for adults with ADHD, issues such as lack of variety in participants in terms of ethnic minorities, short-duration treatment and safety assessment make the interpretation difficult (Weisler, Pandina, Daly, Cooper, & Gassmann-Mayer, 2012). The effect of food on the pharmacokinetics of JNJ-31001074 has been evaluated in a completed phase I trial study in healthy individuals without disclosing the results (NCT00915434). Two individual open-label drug-drug interaction phase I studies are currently in progress for evaluation of the effect of ketoconazole and paroxetine on JNJ-31001074 pharmacokinetics in healthy volunteers (NCT00915746 and NCT01159821). Recently, a multicentre, multinational, randomized, double blind, parallel group and placebo controlled phase II study has been initiated to assess the safety and efficacy of JNJ-31001074 in excessive daytime sleepiness in parkinsonian patients, and is currently recruiting subjects (NCT03194217).