Optimization of 5-Pyridazin-3-one Phenoxypropylamines as Potent, Selective Histamine H3 Receptor Antagonists with Potent Cognition Enhancing Activity

Abstract

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(3)R K(i) = 2.8 nM) and rat H(3)Rs (rH(3)R 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(3)Rs (hH(3)R K(i) = 1.7 nM, rH(3)R 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(3)R 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.