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    • br ABT aR aR methyl

    2022-08-09


    ABT-288 (2-[4'-((3aR,6aR)-5-methyl-hexahydropyrrolo[3,4-b]pyrrol-1-yl)-biphenyl-4-yl]2H-pyridazine-3-one) is a selective H3R antagonist/inverse agonist developed by Abbott. Structurally, it is a compound with molecular weight (MW) 372.46 g/mol, three H-bond acceptors (HBA), and Moriguchi LogP (MLogP) 3.42 (Moriguchi, Hirono, Liu, Nakagome, & Matsushita, 1992), passing all the drug-likeness properties (see Table 2). Moreover, this compound has good pharmacokinetic profile and oral bioavailability as well as a safety profile. ABT-288 induces histamine and Reserpine hydrochloride mg release in vitro, and increases acetylcholine and dopamine levels in rat prefrontal cortex (Esbenshade et al., 2012). ABT-288 is currently in clinical trials and three phase studies have been completed without disclosing the results. A Phase II clinical study (ClinicalTrials.gov Identifier:NCT01018875) has been completed for determining ABT-88 efficacy and safety in adults with mild-to-moderate Alzheimer's disease, it being a randomized, double-blind, active- and placebo-controlled study. The effectiveness of ABT-288 in a randomized, double-blind, placebo-controlled, parallel-group, phase II clinical study for cognitive impairment associated with schizophrenia (CIAS) was also completed in 210 adults with schizophrenia (NCT01077700). A phase I clinical trial for ABT-288 has completed, evaluating safety, tolerability and pharmacokinetics in stable schizophrenic individuals treated with an atypical antipsychotic (NCT00888693). Although the safety and tolerability of ABT-288 have been evidenced in some trials including schizophrenic individuals, healthy young and elderly volunteers (Othman et al., 2012; Othman et al., 2014), its efficacy in Alzheimer's disease and CIAS is still debatable (Haig et al., 2014; Haig et al., 2014), and it seems that large samples are necessary for drawing any strong conclusion (Kubo, Kishi, Matsunaga, & Iwata, 2015). 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 histamine 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).