Several named antagonist ligands have figured noticeably
Several named antagonist ligands have figured noticeably in preclinical studies, with proved clear ability to release neurotransmitters and having efficacy in preclinical animal models. Consequently, this has encouraged ongoing research on improved agents with potency, selectivity, and better drug-likeness to facilitate clinical evaluation. Moreover, computer modeling strategies have been implemented widely, in recent years, for ligand docking and pharmacophore screening purposes (Levoin et al., 2008, Panula et al., 2015, Schlegel et al., 2007). Noticeably, a number of antagonists have advanced to Phase-1 testing and Phase-2 as well as Phase-3 efficacy and safety trials for a number of conditions, including sleep disorders, cognitive disorders in schizophrenia, Alzheimer's disease, Parkinson's disease, ADHD, alcohol addiction, energy homeostasis, epilepsy, diabetic neuropathic pain, Tourette's syndrome, catalepsy, and allergic rhinitis. In search for H3R antagonists, the moderately active H2R antagonist burimamide was found to be an effective H3R antagonist, thus was taken as a lead BMH-21 for further chemical modifications (Arrang et al., 1987, Vollinga et al., 1992). Extensive medicinal chemistry research has resulted in the design and synthesis of imidazole-based H3R antagonists, and before the identification of the H4R, several have been widely used “H3R reference drugs” for preclinical studies, also due to their availability from commercial sources, including thioperamide (35), clobenpropit (36), and ciproxifan (38) (Fig. 5). Thioperamide (35) is highly potent at rat H3R (Arrang et al., 1987, Hill et al., 1997) and has been found broadly effective in vivo in a large number of behavioral models, including elevated plus maze learning (EPM), Morris water maze (MWM), Barnes maze (Komater et al., 2003, Miyazaki et al., 1995) and a variety of epilepsy models. Also, thioperamide demonstrated that H3Rs negatively regulate food intake in rodents, suggesting the therapeutic potential of H3Rs represent a potential target in the treatment of obesity and diabetes mellitus (Masaki et al., 2001, Mollet et al., 2001, Yoshimoto et al., 2006). Interestingly, the latter finding was in agreement with previous studies in which mice with genes disrupted for H1R or histidine decarboxylase (HDC) are prone to becoming obese on a high-fat diet or at advanced age (Masaki et al., 2001, Mollet et al., 2001). Also, several antipsychotic drugs with high antagonist affinities for H1Rs are known to cause weight gain in rodents and humans (Wetterling, 2001). Encouraged by these findings supporting the involvement of central histaminegric system in regulation of food intake and obesity, extensive drug discovery efforts led to the recent development of centrally acting H3R ligands belonging to the bicyclic fused 4H-pyrido[1,2-a]pyrimidin-4-one class with the most promising ligand (42) showing improved pharmacokinetic profile with good in vitro and confirmed oral in vivo potency in rat and mice obesity models (Xiao et al., 2012). Clobenpropit (36) is similarly highly potent in vitro (Eriks et al., 1992, Eriks et al., 1993), and active in vivo, e.g. in models of working memory, seizure, and Alzheimer's disease (Bardgett et al., 2011, Harada et al., 2004, Yokoyama et al., 1994, Zhang et al., 2003). Clobenpropit and thioperamide, however, also have potent activity at H4R (Lim et al., 2009) and thioperamide is, also, active at 5-HT3 receptors (Leurs et al., 1995). Ciproxifan (38) is a potent and selective ligand (Ligneau et al., 1998, Stark et al., 2000) with oral bioavailability, which is operational in a number of preclinical animal experiments and, thus, has received wide-ranging use as an in vivo reference antagonist, for example in attentional models: EEG-assessed waking and impulsivity (Day et al., 2007, Hancock, 2006, Komater et al., 2003, Komater et al., 2005). Moreover, SCH-79687 (37) is a highly potent antagonist that reduced congestion in animal models of allergic rhinitis when co-administered with a H1R antagonist; an evidence supporting the hypothesis that the efficacy of H3R antagonists is referred to peripherally-mediated release of norepinephrine from nasal mucosal H3R as this compound was virtually non-brain penetrant with a brain/plasma ratio of 0.02 (McLeod et al., 2003, Varty and Hey, 2002). For the latter imidazole-based ligands, however, it later has been shown that numerous metabolic interactions may develop due to the ability of the imdazaole heterocycle to potently inhibit CYP450 isoenzymes. Therefore, further chemical optimizations by replacing imidazole with piperidine or tertiary amine resulted in the development of numerous non-imidazole H3R antagonists which attracted the main focus of the H3R antagonist design work in recent years, as these structures demonstrate the class-related issues described with the early generation of imidazole-based agents, including CYP450 inhibition, relatively poor CNS penetration, and incidence of off-target activity at H4R or other receptors (Berlin et al., 2011, Panula et al., 2015). The first SAR study of potent non-imidazole antagonists disclosed UCL-1972 (39) in which the imidazole ring was replaced with a tertiary basic amine (Ganellin et al., 1995). There, also, has been swift progress in the last decade in discovering antagonists with exceptional in vivo efficacy in diverse preclinical experimental models, and numerous non-imidazole antagonist ligands have been described in the literature including pitolisant (40, also earlier known as FUB-649, BF-2.649, BP-2649, or tiprolisant), a ligand of particular interest (Meier et al., 2001). This potent antagonist reached to the clinical trials for a number of indications, and has been well-characterized preclinically as being able to promote wakefulness in animals and humans (Ligneau et al., 2007, Lin et al., 2008, Schwartz, 2011). The orphan indication of narcolepsy as well as excessive day-time sleepiness with Parkinson patients are the actual most prominent indications. Notably, a marketed application (WakixR) for pitolisant has been submitted to the European Medical Agency in 2014. Antagonists with a second basic amine moiety have been widely described as highly potent, with JNJ-5207852 (41) which was reported to promote wakefulness in rat, mouse, and dog models (Barbier et al., 2004, Bonaventure et al., 2007), a property of H3R antagonists as a class (Barbier and Bradbury, 2007). Interestingly, a number of synthetic diamine-containing H3R antagonists have been described with high in vitro potency. The natural product alkaloid conessine (43) is one example of a potent diamine-containing H3R antagonist. In this regard, the core structure has been particularized to analogs, while the potency and commercial availability of conessine itself suggest potential utility as a tool compound (Cowart et al., 2004, Santora et al., 2008a, Santora et al., 2008b, Zhao et al., 2008). Furthermore, the benzofuran ABT-239 (44) has been widely used as a standard antagonist with high in vivo potency in a number of animal models of attention, ethanol-associated learning deficit, cognition, schizophrenia, and Alzheimer's disease (Bitner et al., 2010, Cowart et al., 2005, Fox et al., 2005, Varaschin et al., 2010). Also, GSK-189254 (45) has been described as largely effective in a number of animal experiments, including attentional, memory, pain and narcolepsy models (Guo et al., 2009, McGaraughty et al., 2012, Medhurst et al., 2007). Noticeably, GSK-189254 (45) has also been synthesized in an 11C-labeled form and has been used as a PET tracer to empirically quantify H3R occupancy of test compounds in intact animals and in the clinic (Ashworth et al., 2010). Also, GSK-207040 (46) and GSK-334329 (47) were both found effective in models of scopolamine-induced memory impairment, neuropathic pain, and capsaicin-induced tactile allodynia (Ashworth et al., 2010, Medhurst et al., 2007). Importantly, CEP-26401 (46, irdabisant), a first-generation pyridazinone candidate advanced into clinical trials for cognition and sleep-wake indications (Hudkins et al., 2015, Hudkins et al., 2011, Raddatz et al., 2012). Moreover, several reports figured out an efficacy in an osteoarthritis pain model for ABT-239 (44) and GSK-334429 (47) (Hsieh et al., 2010). Recently, the compound JNJ-39220675 (48) was found to decrease voluntarily ethanol intake in ethanol-preferring rats (Galici et al., 2011), and to have decongestant efficacy in an early clinical trial in subjects with allergic rhinitis (Fig. 5) (Barchuk et al., 2013). Moreover, ST-1283 (49) and very recently DL77 (50) confirmed the findings on reduction of voluntary alcohol intake and ethanol-induced conditioned place preference in mice (Bahi et al., 2015, Bahi et al., 2013). However, it seems obvious that specificity profiles are missing for many tested H3R ligands indicating that preclinical data should be considered with great caution.