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    • MK cyclobutylpiperidin yl oxyphenyl methyl

    2022-01-20

    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 Senexin A (Sun et al., 2013) (NCT01092780). With LML-134 (1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate) containing drug-likeness properties (MW 375.47, five HBA, and MLogP 1.88), Novartis presents an additional drug-candidate to treat excessive sleepiness. A phase I clinical study was performed in 2015 with pending results (NCT02334449). Despite the lacking results from clinics, first pharmacological and chemical information about this entity was published recently (Troxler et al., 2019). These results demonstrate low nanomolar H3R binding affinity and potent abrogation of R-(α)-methylhistamine mediated inhibition of cAMP-formation in vitro. In addition, the authors present first pharmacokinetic data including promising blood-brain permeability properties that lead to high levels of receptor occupancy (about 90%) after peroral administration. Two H3R antagonists were introduced by Pfizer in 2011, namely PF-03654746 and PF-03654764 (Wager et al., 2011). The former, under the chemical name of trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidinylmethyl)-phenyl]cyclobutanecarboxamide, is a drug-like molecule (Table 2) with MW 322.39, four HBA, one HBD, and MLogP 3.2. A scalable process was developed for the synthesis of this drug candidate (Hawkins et al., 2012). The result of pre-clinical binding assays showed that PF-03654746 binds to recombinant human and rat H3Rs with high affinity (Wager et al., 2011). Recently, receptor occupancy studies using [11C]-GSK-189254 PET imaging in healthy human subjects revealed that PF-03654746 fully occupies H3R binding sites (Gallezot et al., 2017). At present, PF-03654746 is involved in five clinical trial studies. The compound has been evaluated in a randomized, double blind, double dummy, placebo controlled, four way cross-over phase II study for its nasal decongestant properties in the treatment of allergic rhinitis (NCT00562120). The results are indicative of PF-03654746 efficacy in reducing allergen-induced nasal symptoms in combination with fexofenadine (Stokes et al., 2012). The efficacy and safety of PF-03654746 has also been assessed in a randomized, double-blind, crossover phase II study for patients with ADHD (NCT00531752). Furthermore, PF-03654746 has been evaluated in a completed phase I study for the treatment of cognitive deficits in schizophrenia, although no results have been disclosed (NCT01346163). The effect of PF-03654746 in EDS associated with narcolepsy has been determined in a randomized phase II, double blind, placebo-controlled, multi-center crossover study (NCT01006122). A trial for determining receptor occupancy of PF-03654746 in a healthy-volunteer PET study has been completed without disclosing any outcome but as well probed the qualification of a further radiolabeled ligand [11C]-PF-04621053 by Pfizer with no disclosed structure (NCT00730990).