Synthesis and evaluation of pyridazinone–phenethylamine derivatives as selective and orally bioavailable histamine H3 receptor antagonists with robust wake-promoting activity

A series of pyridazinone–phenethylamine derivatives with moderate to low nanomolar affinity for rat and human H3R are described. These analogs exhibited excellent selectivity and metabolic stability, with acceptable rat pharmacokinetic properties. In vivo, 7 and 11 demonstrated potent H3R functional antagonism in the rat dipsogenia model and robust wake-promoting activity in the rat electroencephalogram/electromyography (EEG/EMG) model.

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