Synthesis and evaluation of pyridazinone-phenethylamine derivatives as selective and orally bioavailable histamine H sub(3 receptor antagonists with robust wake-promoting activity)

A series of pyridazinone-phenethylamine derivatives with moderate to low nanomolar affinity for rat and human H sub(3R are described. These analogs exhibited excellent selectivity and metabolic stability, with acceptable rat pharmacokinetic properties. In vivo, 7 and 11 demonstrated potent H) sub(3)R functional antagonism in the rat dipsogenia model and robust wake-promoting activity in the rat electroencephalogram/electromyography (EEG/EMG) model.