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  • Allergic rhinitis characterized by inflammation of the

    2022-01-20

    Allergic rhinitis, characterized by inflammation of the nasal membrane, results from an over-activated immune system exposed to fty720 in sensitized individuals, and is associated with nasal congestion, rhinorrhea, sneezing, and pruritus. As histamine is a key mediator in triggering allergic rhinitis, preventing the histamine action is a priority in these conditions. Currently, H1 receptor antagonists are extensively utilized for allergic rhinitis; however, in most cases for fully alleviating nasal congestion they are administered alongside α-adrenergic agonists. Since side-effects such as stimulatory CNS and cardiovascular actions have been observed following the administration of α-adrenergic agonists (Berlin et al., 2011; Leurs et al., 2005), designing compounds having fewer side-effects seems beneficial. The function of H3Rs in controlling allergic rhinitis has been widely documented and anti-allergic features of H3R antagonists via noradrenaline release have been reported in several studies (Berlin et al., 2011; McLeod et al., 1999; Repka-Ramirez, 2003; Varty, Gustafson, Laverty, & Hey, 2004). Based on these findings, co-administration of antagonists at H1 and H3 receptors may be a useful alternative to the current pharmacotherapy. On the other hand, the molecular design of hybrid compounds with dual activity on H1 and H3 receptors would be attractive for allergic rhinitis conditions. An inflammatory disease resulting from demyelination and neurodegeneration in CNS is multiple sclerosis (MS), affecting especially young adults and adolescents (Jadidi-Niaragh & Mirshafiey, 2010; Tiligada, Kyriakidis, Chazot, & Passani, 2011). There is evidence indicating that histamine has a regulatory function in experimental allergic encephalomyelitis (EAE), an autoimmune model of MS. Accordingly, targeting H3Rs can be a useful strategy for preventing MS progression (Kremer, Kury, & Dutta, 2015; Schwartzbach et al., 2017). Apart from aforementioned clinical indications discussed above, recent preclinical studies evidenced the effectiveness of H3 antagonists in glaucoma and traumatic brain injury in animal models (Lanzi et al., 2019; Liao et al., 2019). A list of H3R antagonists/inverse agonists currently being investigated in ongoing clinical studies including their clinical status, phase of development, and therapeutic indications along with the corresponding physicochemical and drug-likeness properties is provided in Fig. 3, Tables 1 and 2, and this information is briefly discussed in next section.
    ABT-288 (2-[4'-((3aR,6aR)-5-methyl-hexahydropyrrolo[3,4-b]pyrrol-1-yl)-biphenyl-4-yl]2H-pyridazine-3-one) is a selective H3R antagonist/inverse agonist developed by Abbott. Structurally, it is a compound with molecular weight (MW) 372.46 g/mol, three H-bond acceptors (HBA), and Moriguchi LogP (MLogP) 3.42 (Moriguchi, Hirono, Liu, Nakagome, & Matsushita, 1992), passing all the drug-likeness properties (see Table 2). Moreover, this compound has good pharmacokinetic profile and oral bioavailability as well as a safety profile. ABT-288 induces histamine and acetylcholine release in vitro, and increases acetylcholine and dopamine levels in rat prefrontal cortex (Esbenshade et al., 2012). ABT-288 is currently in clinical trials and three phase studies have been completed without disclosing the results. A Phase II clinical study (ClinicalTrials.gov Identifier:NCT01018875) has been completed for determining ABT-88 efficacy and safety in adults with mild-to-moderate Alzheimer's disease, it being a randomized, double-blind, active- and placebo-controlled study. The effectiveness of ABT-288 in a randomized, double-blind, placebo-controlled, parallel-group, phase II clinical study for cognitive impairment associated with schizophrenia (CIAS) was also completed in 210 adults with schizophrenia (NCT01077700). A phase I clinical trial for ABT-288 has completed, evaluating safety, tolerability and pharmacokinetics in stable schizophrenic individuals treated with an atypical antipsychotic (NCT00888693). Although the safety and tolerability of ABT-288 have been evidenced in some trials including schizophrenic individuals, healthy young and elderly volunteers (Othman et al., 2012; Othman et al., 2014), its efficacy in Alzheimer's disease and CIAS is still debatable (Haig et al., 2014; Haig et al., 2014), and it seems that large samples are necessary for drawing any strong conclusion (Kubo, Kishi, Matsunaga, & Iwata, 2015).