The only approved H R antagonist inverse agonist is BF
The only approved H3R antagonist/inverse agonist is BF2.649 (1- 3-[3-(4-chlorophenyl)propoxy]propyl piperidine), developed by Bioprojet and known as pitolisant (Wakix®). It was approved by the European Medicines Agency in March 2016 and marketed in the European Union to be used in narcolepsy with or without cataplexy (Kollb-Sielecka et al., 2017; Syed, 2016). From a structural view, pitolisant is a non-imidazole based antagonist, which was rationally synthesized based on the structural modification by imidazole replacement with a piperidine group (Meier et al., 2001). As for other compounds containing imidazole moiety that interact with CYP450 enzymes, replacement with a piperidine ring reduced the hepatic toxicities (Ligneau et al., 2007). Pitolisant covers all the drug-likeness properties with MW 295.85, two HBA and MLogP 3.53 (Table 2). This compound displayed selectivity for the H3R over the other three histamine receptors. Preliminary in vivo preclinical studies showed that pitolisant enhanced cerebral Nτ-methylhistamine levels in rodent models with good oral M344 and brain penetration (Ligneau, Perrin, et al., 2007). Additionally, the activity of rat prefrontal cortical dopaminergic and cholinergic pathways was increased by the intraperitoneal administration of pitolisant (Ligneau et al., 2007; Ligneau, Perrin, et al., 2007). The more important effect of pitolisant is related to its wake-promoting and arousal activities as a result of enhanced histamine release in animal models (Ligneau, Perrin, et al., 2007). Moreover, its potential in the treatment of severe excessive daytime sleepiness (EDS) in narcoleptic teenagers refractory to therapeutic agents (e.g. modafinil and methylphenidate) was evaluated and the findings indicate its capability to significantly diminish sleepiness after the administration of a single dose (Inocente et al., 2012). In another study by Leu-Semenescu et al., the pitolisant efficacy in patients with symptomathic idiopathic hypersomnia refractory to current stimulants was assessed showing increased activity of the histaminergic neurons in such patients (Leu-Semenescu, Nittur, Golmard, & Arnulf, 2014). Moreover, preclinical investigations show useful effects of pitolisant on EDS in orexin-/- mice and narcoleptic patients (Lin et al., 2008). Pitolisant has also been shown to improve consolidation processes in mouse fear memory (C. Brabant, Charlier, & Tirelli, 2013). Furthermore, the application of pitolisant for sleep-deficits in Prader-Willi syndrome has been demonstrated in mouse-models and described as off-label use, though this has not been investigated in interventional clinical trials yet (Balzani, Pace, Falappa, & Tucci, 2017; Falappa et al., 2018; Ghergan et al., 2017; Pace et al., 2018; Pullen, Picione, Tan, Johnston, & Stark, 2018; Pullen, Picione, Tan, Johnston, & Stark, 2019). A suppressive effect of pitolisant on epileptiform discharges in photosensitive patients with epilepsy was observed following the administration of a single dose, suggesting effectiveness in the treatment of both partial and generalized chronic seizures (Kasteleijn-Nolst Trenité et al., 2013). Further, a phase II study showed some benefit with pitolisant as adjunctive for patients suffering from epilepsy (Collart Dutilleul et al., 2016). Additional indication of pitolisant has been prompted for disorders as Guilles de la Tourette syndrome and autism that often are comorbidities with epileptic disorders (Hartmann, Martino, & Murphy, 2016). In another study, the effect of pitolisant on side-effects associated with olanzapine at the initial period of administration in mice was monitored, and the results indicated a reduction in olanzapine-induced sedation and depression-like symptoms (Dudek et al., 2016). Recently, the anti-obesity activity of pitolisant has been evaluated in terms of controlling body weight in obese mice. The results of this investigation supported its effectiveness in lowering plasma glucose and triglyceride levels by improving glucose tolerance and lipid profile (Kotanska, Kuder, Szczepanska, Sapa, & Kiec-Kononowicz, 2018). From a toxicity point of view, a non-clinical cardiovascular safety assessment was conducted for pitolisant and the results revealed lack of QT-liability and proarrhythmic risk according to International Conference on Harmonization (ICH) guidelines (Ligneau et al., 2017). The abuse liability of pitolisant was also tested in different in vivo rodent models and the outcome of the studies showed no addictive potential (Christian Brabant, Charlier, Navacerrada, Alleva, & Tirelli, 2016; Uguen et al., 2013).