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  • With LML methyl oxo dihydropyridazin yl piperidin yl

    2022-01-14

    With LML-134 (1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate) containing drug-likeness properties (MW 375.47, five HBA, and MLogP 1.88), Novartis presents an additional drug-candidate to treat excessive sleepiness. A phase I clinical study was performed in 2015 with pending results (NCT02334449). Despite the lacking results from clinics, first pharmacological and chemical information about this entity was published recently (Troxler et al., 2019). These results demonstrate low nanomolar H3R binding affinity and potent abrogation of R-(α)-methylhistamine mediated inhibition of cAMP-formation in vitro. In addition, the authors present first pharmacokinetic data including promising blood-brain permeability properties that lead to high levels of receptor occupancy (about 90%) after peroral administration. Two H3R antagonists were introduced by Pfizer in 2011, namely PF-03654746 and PF-03654764 (Wager et al., 2011). The former, under the chemical name of trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidinylmethyl)-phenyl]cyclobutanecarboxamide, is a drug-like molecule (Table 2) with MW 322.39, four HBA, one HBD, and MLogP 3.2. A scalable process was developed for the synthesis of this drug candidate (Hawkins et al., 2012). The result of pre-clinical binding assays showed that PF-03654746 binds to recombinant human and rat H3Rs with high affinity (Wager et al., 2011). Recently, receptor occupancy studies using [11C]-GSK-189254 PET imaging in healthy human subjects revealed that PF-03654746 fully occupies H3R Ceftazidime (Gallezot et al., 2017). At present, PF-03654746 is involved in five clinical trial studies. The compound has been evaluated in a randomized, double blind, double dummy, placebo controlled, four way cross-over phase II study for its nasal decongestant properties in the treatment of allergic rhinitis (NCT00562120). The results are indicative of PF-03654746 efficacy in reducing allergen-induced nasal symptoms in combination with fexofenadine (Stokes et al., 2012). The efficacy and safety of PF-03654746 has also been assessed in a randomized, double-blind, crossover phase II study for patients with ADHD (NCT00531752). Furthermore, PF-03654746 has been evaluated in a completed phase I study for the treatment of cognitive deficits in schizophrenia, although no results have been disclosed (NCT01346163). The effect of PF-03654746 in EDS associated with narcolepsy has been determined in a randomized phase II, double blind, placebo-controlled, multi-center crossover study (NCT01006122). A trial for determining receptor occupancy of PF-03654746 in a healthy-volunteer PET study has been completed without disclosing any outcome but as well probed the qualification of a further radiolabeled ligand [11C]-PF-04621053 by Pfizer with no disclosed structure (NCT00730990). A compound 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 Ceftazidime 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).