Novel heterocyclic-substituted benzofuran histamine H3 receptor antagonists: in vitro properties, drug-likeness, and behavioral activity.

Three novel heterocyclic benzofurans A-688057 (1), A-687136 (2), and A-698418 (3) were profiled for their in vitro and in vivo properties as a new series of histamine H3 receptor antagonists. The compounds were all found to have nanomolar potency in vitro at histamine H3 receptors, and when profiled in vivo for CNS activity, all were found active in an animal behavioral model of attention. The compound with the most benign profile versus CNS side effects was selected for greater scrutiny of its in vitro properties and overall drug-likeness. This compound, A-688057, in addition to its potent and robust efficacy in two rodent behavioral models at blood levels ranging 0.2–19nM, possessed other favorable features, including high selectivity for H3 receptors (H3, Ki=1.5nM) versus off-target receptors and channels (including the hERG K+ channel, Ki>9000nM), low molecular weight (295), high solubility, moderate lipophilicity (logDpH7.4=2.05), and good CNS penetration (blood/brain 3.4×). In vitro toxicological tests indicated low potential for phospholipidosis, genotoxicity, and CYP450 inhibition. Even though pharmacokinetic testing uncovered only moderate to poor oral bioavailability in rat (26%), dog (30%), and monkey (8%), and only moderate blood half-lives after i.v. administration (t1/2 in rat of 2.9h, 1.7h in dog, 1.8h in monkey), suggesting poor human pharmacokinetics, the data overall indicated that A-688057 has an excellent profile for use as a pharmacological tool compound.