Arena Pharmaceutical introduced a biaryl sulfone derivative
Arena Pharmaceutical introduced a biaryl sulfone derivative with antagonistic activity at H3Rs known as APD-916, ((R)-1-(2-(4'-(3-methoxypropylsulfonyl)biphenyl-4-yl)ethyl)-2-methylpyrrolidine), which was rationally designed from corresponding sulfonamides in order to yield compounds with short duration of action (Semple et al., 2012). All the drug-likeness features have been observed for APD-916 with MW 401.56 g/mol, four HBA and MLogP 3.32. Good pharmacokinetic profiling as well as high selectivity over other HO-3867 receptors have been reported for this drug candidate in preclinical studies. Orally administrated APD-916 enhanced wakefulness in different animal models (Semple et al., 2012), and there is a single ongoing clinical trial assessing APD-916 based on its tolerability and pharmacokinetics in healthy adult individuals in a randomized, double-blind, placebo-controlled, single-dose escalation phase I study (NCT01093508). AZD5213, (4-((1S,2S)-2-(4-Cyclobutylpiperazine-1-carbonyl)cyclopropyl)benzamide) developed by AstraZeneca, is an antagonist at H3Rs passing the Lipinski's rules of five criteria (i.e. MW 327.42 g/mol; HBA 3; HBD 1; MLogP 1.84). Additionally, this drug candidate fulfills all other drug-likeness and lead-likeness criteria listed in Table 2. Currently, seven clinical trial studies have been completed for this candidate. Three of them successfully accomplished phase I including safety, tolerability, and pharmacokinetics of AZD5213 after single and multiple oral doses in healthy volunteers in a double-blind, randomized, placebo-controlled, parallel-group assessment (NCT01171105, NCT01121302, and NCT01335451). Another study was conducted to determine H3R occupancy (RO) of AZD5213 using a radiolabeled ligand following single-dose oral administration in healthy subjects. The results showed that AZD5213 binds to H3Rs in a saturable, dose-, and concentration-dependent manner. Reported diurnal fluctuations of AZD5213 (i.e. high daytime and low night-time RO) make it suitable to be used during daytime with procognitive efficacy without sleep disruption in night-time (Jucaite et al., 2013) (NCT01194986). AZD5213 has also been evaluated in three phase II trials for a variety of clinical indications: a multi-center, randomized, two-part study for assessing safety, tolerability and efficacy of AZD5213 in subjects with painful diabetic neuropathy receiving pregabalin (NCT01928381); a randomized double-blind, multi-center, placebo-controlled study for testing AZD5213 on sleep duration in individuals with Alzheimer's/cognitive impairment (NCT01548287); and a two-part- randomized, multi-center, blinded study for evaluating safety, tolerability, pharmacokinetic and efficacy of AZD-5213 in patients with Tourette's syndrome (NCT01904773). A series of positron emission tomography (PET)-suitable congeners of AZD5213 have been presented recently, including [11C]-carbonyl labeled AZD5213 as well as [11C]-AZ13153556 and [11C]-AZ13198083, being evaluated regarding brain uptake and distribution in non-human primates (Dahl et al., 2018). 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 absorption 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).