SCH is a H R receptor

SCH-497079 is a H3R receptor antagonist introduced by Schering-Plough, without any publicized pharmacological and structural information. A Phase II clinical trial assessment of SCH-497079 on weight has been completed in a multicenter, randomized, parallel-group and placebo-controlled study in obese and over-weight participants (NCT00642993). A further study evaluates the effect of SCH-497079 on the metabolic profile and therapeutic response in a population with different race/ethnic origin bearing type 2 TAPI-1 in a randomized, placebo-controlled and three-way crossover study (NCT00673465). Recently, a novel H3R antagonist named SUVN-G3031, (N-[4-(1-cyclobutylpiperidin-4-yl)oxyphenyl]-2-morpholin-4-ylacetamide), and developed by Suven Life Sciences has entered into clinical trial studies (Hung & Fu, 2017). From a structural point of view, this drug candidate possesses all the features needed for drug-likeness criteria (Table 2) with MW 373.49 g/mol, five HBA, one HBD, and MLogP 1.43. Two phase I clinical trial studies are ongoing; in the first study, safety, tolerability and pharmacokinetics of SUVN-G3031 in healthy volunteers are investigated in a single-center, double-blind, placebo-controlled, randomized study (NCT02342041), while in the second study, the pharmacokinetic profile of SUVN-G3031 is assessed with respect to food, gender, and age (NCT02881294). Recently, the results of first clinical trial study (i,e, NCT02342041) has been presented and the findings showed that SUVN-G3031 is well-tolerated in healthy subjects with favorable safety and pharmacokinetic profile (Nirogi, Shinde, et al., 2019). In addition, preclinical studies for SUVN-G3031 in treatment of narcolepsy are being conducted and the results are indicative of potential efficacy of this therapeutic agent in sleep disorders (Bhayrapuneni et al., 2019; Nirogi, Bhyrapuneni, et al., 2019).
Although there are growing bodies of research dealing with diverse non-imidazole based compounds, they are not free from obstacles in their development pipeline and hence the design of these compounds is complicated by various factors briefly discussed below. One of the problems in designing H3R antagonist/inverse agonists is the affinity of these agents towards the hERG K+ channel, resulting in cardiotoxicity and originated from the similarity between the H3R pharmacophore and hERG K+channels (Gemkow et al., 2009; Lazewska & Kiec-Kononowicz, 2010; Łażewska & Kieć-Kononowicz, 2014; Tiligada et al., 2009). Phospholipidosis is an additional concern for non-imidazole-based compounds containing two basic sites (Gemkow et al., 2009; Lazewska & Kiec-Kononowicz, 2010; Łażewska & Kieć-Kononowicz, 2014). Prolonged duration of action as a consequence of high CNS penetration, lipophilicity, plasma protein binding and residence time, is a drawback for some non-imidazole compounds, leading to insomnia derived from a wake-promoting side-effect. This is one of the reasons for withdrawal of H3R ligands from clinical trials (Łażewska & Kieć-Kononowicz, 2014; Singh & Jadhav, 2013). Therefore, receptor occupancy should be considered in pre-clinical studies as occupancy over 80% induces insomnia and in this context paying attention to dose schemes of drug candidates in clinical investigations is critical (Kuhne et al., 2011). Another approach to resolve this obstacle may be the characterization of ligands concerning the duration of H3R blockade and to develop ligands with short to intermediate receptor residence times (Mocking, Verweij, Vischer, & Leurs, 2018). While screening of drug-target residence times is currently emerging to give additional information about the time-course of receptor-dissociation and the duration of target-occupancy, only some of the above-mentioned H3R ligands have been recently characterized in this context (Mocking et al., 2018; Reiner & Stark, 2019; Riddy et al., 2019). Being substrates for P-glycoprotein is a problem reported for some non-imidazole-based compounds (Gemkow et al., 2009; Lazewska & Kiec-Kononowicz, 2010). Apart from this, it should be kept in mind that developing H3R antagonist/inverse agonists is greatly affected by the complex pharmacology of H3Rs. Molecular heterogeneity of different splice variants, constitutive activity, receptor oligomerization, differential signaling pathways and species-related discrepancies are determinant parameters that debilitate the design process (Bhowmik et al., 2012; Esbenshade et al., 2008; Lazewska & Kiec-Kononowicz, 2010; Łażewska & Kieć-Kononowicz, 2014; Plancher, 2011; Riddy et al., 2017; Tiligada et al., 2011; Wijtmans et al., 2007). Therefore, based on the available structural information responsible for shortcomings and failures of H3R antagonists/inverse agonists, special notice should be paid in the rational design of such compounds. Additionally, for the appropriate assessment of new chemical entities, it has been suggested that the biological assays be performed in different functional platforms containing multiple H3R isoforms (Lazewska & Kiec-Kononowicz, 2010).