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    • The H R antagonist JNJ developed by Johnson Johnson has

    2022-08-08

    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 cid calculator 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. MK-3134 (3-[4-(1-cyclobutylpiperidin-4-yl)oxyphenyl]-2-methyl-5-(trifluoromethyl)quinazolin-4-one) was synthesized by Merck, as the structurally constrained analogue of MK-0249 (Nagase et al., 2008). This H3R inverse agonist has MW 457.49, seven HBA, and MLogP 4.58, with one violation in terms of drug-likeness criteria observed for Lipinski, Ghose, and Egan rules (see Table 2 for more details). MK-3134 has high binding affinity and selectivity towards H3Rs. Moreover, this compound showed good pharmacokinetic profile in rat models (Nagase et al., 2008). Receptor occupancy using [11C]-MK-8278 as radiotracer in PET scan revealed high occupation of cerebral H3Rs by this inverse agonist (Van Laere et al., 2014). Three phase I studies involving MK-3134 are currently underway. One of the trial studies examined the effectiveness of MK-3134 in combination with donepezil in scopolamine-induced cognitive impairment using a five-period, placebo-controlled, cross-over study (NCT01181310). The outcome of this study indicates that the combination of MK-3143 and donepezil can reverse the scopolamine-induced impairment to a larger extent compared with each therapeutic agent alone (Cho et al., 2011). Additionally, a clinical trial has dealed with the electroencephalogram platform standardization of MK-3134 in healthy individuals in a double blind, randomized, crossover study (NCT01110616). Furthermore, MK-3134 has been investigated in a 4-period, placebo-controlled, cross-over study to assess the use of functional magnetic resonance imaging (fMRI) and cerebral blood flow measurements as biomarkers for measuring MK-3134-induced changes in dementia (NCT00887601). However, at this stage the findings of two latter trial studies are not publicly available. An additional H3R inverse agonist developed by Merck is MK-7288 (2'-methoxy-N-methyl-7'-oxo-N-[2-(1-piperidinyl)ethyl]-7'H-spiro[cyclohexane-1,5'-furo[3,4-b]pyridine]-4-carboxamide) with drug-likeness properties (MW 401.5, six HBA, and MLogP 1.98). A phase I clinical trial has been completed for this drug candidate to evaluate its effectiveness and pharmacodynamics in EDS in subjects with obstructive sleep apnea (Sun et al., 2013) (NCT01092780).