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  • An azabicyclic compound named S a a hexahydro H

    2022-06-22

    An azabicyclic Irinotecan HCl Trihydrate receptor named S 38093, (4-[3-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)propoxy]benzamide), was introduced by Servier with H3R antagonist and inverse agonist activity (Sors et al., 2017). The compound contains all the drug-likeness criteria owing to its physicochemical properties (i.e. MW 288.38, HBA 3, HBD 1, and MLogP 2.15; Table 2). In vitro preclinical studies demonstrated moderate affinity of S 38093 for human and rodent H3Rs but high selectivity relative to other histamine receptors (Sors et al., 2017). S 38093 also showed a good pharmacokinetic profiling in animal models (Panayi et al., 2017; Sors et al., 2017). In addition to the moderate affinity of S 38093 observed in vitro, a 30-fold higher affinity was observed at sigma-1 receptors that may therefore be involved in its potent cognition enhancing effects (Riddy et al., 2019). Furthermore, improved cholinergic neurotransmission and higher histamine turn-over were observed in animal models, suggesting a cognitive enhancement property for this agent (Panayi et al., 2017). Surprisingly, in a recent study the chronic administration of S 38093 to adult animals in a mouse model of Alzheimer's disease induced hippocampal neurogenesis, possibly due to the release of growth factors (Guilloux et al., 2017). Moreover, a synergistic effect of S 38093 in elevating memory performance was evidenced when co-administered with donepezil in middle-aged mice (Sors et al., 2016). An antinociceptive effect of S 38093 was also observed in different neuropathic pain rat models following chronic administration (Chaumette et al., 2018). The only registered clinical trial reported for S 38093 is assessing its efficacy and safety in subjects with mild to moderate Alzheimer's disease (ISRCTN89039808). In 2012, Sanofi-Aventis developed a compound, SAR-110894, as H3R antagonist/inverse agonist (Griebel et al., 2012). No physicochemical properties are publicly available nor has the structure been disclosed. In preclinical studies SAR-110894 displayed high potency and selectivity for recombinant and native human H3Rs. In addition, effectiveness of SAR-110894 in different cognitive impairment animal models related to Alzheimer's disease, ADHD, and schizophrenia was evidenced (Griebel, Pichat, et al., 2012). In addition, the awakening characteristic of SAR-110894 was investigated using EEG recordings in rats during the light phase. Although this drug candidate failed to significantly modify the sleep/wakefulness profile, this can be an advantage over other similar H3R antagonists in cognitive disorders owing to its non-wakefulness property during night-time (Griebel, Decobert, Jacquet, & Beeske, 2012). Recently, the beneficial effect of SAR-110894 in inhibiting tau pathology and cognitive deficit has been documented in transgenic mouse model of tauopathy (Delay-Goyet et al., 2016). SAR-110894 is currently under investigation in a multinational, multicenter, randomized, double-blind, parallel-group, placebo-controlled phase II clinical trial involving subjects with mild to moderate Alzheimer's disease receiving donepezil (NCT01266525). 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 diabetes mellitus 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).