Optimization of 5-pyridazin-3-one phenoxypropylamines as potent, selective histamine H _3 receptor antagonists with potent cognition enhancing activity

摘要

Previous studies have shown that (5-{4-[3-(R)-2-methylpyrrolin-1-yl- propoxy]phenyl}-2H-pyridazin-3-one) 2 had high affinity for both the human (hH _3R K _i = 2.8 nM) and rat H _3Rs (rH _3R K _i = 8.5 nM) but displayed low oral bioavailability in the rat. Optimization of the 5-pyridazin-3-one R 2 and R 6 positions to improve the pharmacokinetic properties over 2 led to the identification of 5-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2-pyridin- 2-yl-2H-pyridazin-3-one 29. Compound 29 displayed high affinity for both human and rat H _3Rs (hH _3R K _i = 1.7 nM, rH _3R K _i = 3.7 nM) with a greater than 1000-fold selectivity over the other histamine receptor subtypes and favorable pharmacokinetic properties across species (F = 78% rat, 92% dog, 96% monkey). It showed low binding to human plasma proteins, weakly inhibited cytochrome P450 isoforms, and displayed an excellent safety profile for a CNS-active compound. 29 displayed potent H _3R antagonist activity in the brain in a rat dipsogenia model and demonstrated enhancement of cognitive function in a rat social recognition model at low doses. However, the development of compound 29 was discontinued because of genotoxicity.