Synthesis and structure-activity relationship of 5-pyridazin-3-one phenoxypiperidines as potent, selective histamine H3 receptor inverse agonists

Optimization of the R2 and R6 positions of (5-{4-[3-(R)-2-methylpyrrolin-1-yl-propoxy]phenyl}-2H-pyridazin-3-one) 2a with constrained phenoxypiperidines led to the identification of 5-[4-(cyclobutyl-piperidin-4-yloxy)-phenyl]-6-methyl-2H-pyridazin-3-one 8b as a potent, selective histamine H3 receptor antagonist with favorable pharmacokinetic properties. Compound 8b had an excellent safety genotoxocity profile for a CNS-active compound in the Ames and micronucleus tests, also displayed potent H3R antagonist activity in the brain in the rat dipsogenia model and robust wake activity in the rat EEG/EMG model.