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  • A compound structurally similar to PF

    2021-11-25

    A JNJ26481585 sale structurally similar to PF-03654746 has been developed by Pfizer (PF-03654764), with a minor change in the substituent attached to the cyclobutanecarboxamide moiety (Wager et al., 2011). This compound, with the chemical name trans-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-N-(2-ethylpropyl)cyclobutanecarboxamide possesses all the drug-likeness properties (MW 350.45, HBA 4, HBD 1, and MLogP 3.65). Binding assays showed high affinity and selectivity towards H3Rs with excellent ADME properties (Wager et al., 2011). Likewise PF-03654746, this candidate has completed a phase II trial study for investigating its efficacy in allergic rhinitis in a randomized, double blind, placebo controlled, and four way cross-over study (NCT01033396). However, no significant reduction in allergic rhinitis-associated nasal symptoms was observed compared to the combination of fexofenadine and pseudoephedrine (North et al., 2014). In another trial study, the safety, tolerability, and pharmacokinetics of PF-03654764 in healthy individuals were assessed in a randomized, double blind, placebo controlled, and dose escalation study following oral administration (NCT00989391). An azabicyclic compound 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 Genomic (chromosomal) DNA clone 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).