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  • LIMKi 3 australia A second H R antagonist with

    2022-01-06

    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 LIMKi 3 australia 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). The H3R antagonist JNJ-17216498, developed by Johnson & Johnson, has entered clinical trial studies, but no information regarding its structure has been publicized to date. A phase II study of JNJ-17216498 monotherapy has been completed for patients with narcolepsy, but the results are not publically available concerning the efficacy and safety of JNJ-17216498 compared to modafinil and placebo (NCT00424931). Merck introduced in 2008 a quinazoline-based H3R antagonist/inverse agonist known as MK-0249 (2-methyl-3-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-5-(trifluoromethyl)quinazolin-4-one) with MW 431.45g/mol and seven HBA (Nagase et al., 2008). This compound contains all the drug-likeness properties with one violation in Lipinski rule of five (i.e. MLogP 4.17. marginally greater than the predefined value of 4.15) (Table 2). In vitro radioligand binding assays showed that this candidate has high affinity at human H3Rs with antagonist activity. Moreover, an in vivo study showed increased brain histamine levels following oral administration of MK-0249 in rats (Nagase et al., 2008). At the moment, three clinical trial Phase II evaluations have been completed in order to assess the safety and efficacy of MK-0249 in subjects with paranoid schizophrenia (NCT00506077), Alzheimer's disease (NCT00420420), and ADHD (NCT00475735) in a randomized, double-blind, placebo-controlled study. However, for all indications no significant efficacy was observed (Egan et al., 2012; Egan et al., 2013; Herring et al., 2012). Considering the shortcomings of these studies, such as selection of appropriate dose, duration of treatment, sample size, and inclusion of patients with concomitant use of therapeutic agents (Egan et al., 2012; Egan et al., 2013; Herring et al., 2012), the interpretation of the results should be carefully handled and in some cases further evaluations seems to be essential.