Synthesis and SAR of 5-Amino- and 5-(Aminomethyl)benzofuran Histamine H<INF>3</INF> Receptor Antagonists with Improved Potency

A new series of H<INF>3</INF> receptor antagonists was discovered with nanomolar and subnanomolar affinities at human and rat H<INF>3</INF> receptors. Starting from an earlier, more structurally limited series of benzofurans, the present series of compounds demonstrated increased structural variety and flexibility with greater in vitro potency. One compound in particular, {2-[2-(2-(R)-methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl}(5-nitropyridin-2-yl)amine (<BO>7h</BO>), gave the best binding potency (human K<INF>i</INF> of 0.05 nM, rat K<INF>i</INF> of 0.11 nM), which represented a 9-fold (in human) and an 11-fold (in rat) improvement over ABT-239 (compound <BO>5</BO>), a compound previously reported to have excellent in vitro potency and in vivo efficacy. The synthesis, SAR of the H<INF>3</INF> binding affinities, in vitro assay for phospholipidosis, and pharmacokinetic properties of the new compounds are described.