1005402-41-4Relevant academic research and scientific papers
Optimization of 5-pyridazin-3-one phenoxypropylamines as potent, selective histamine H3 receptor antagonists with potent cognition enhancing activity
Tao, Ming,Aimone, Lisa D.,Huang, Zeqi,Mathiasen, Joanne,Raddatz, Rita,Lyons, Jacquelyn,Hudkins, Robert L.
, p. 414 - 423 (2012/03/11)
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 (hH3R Ki = 2.8 nM) and rat H3Rs (rH 3R Ki = 8.5 nM) but displayed low oral bioavailability in the rat. Optimization of the 5-pyridazin-3-one R2 and R6 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 H3Rs (hH3R Ki = 1.7 nM, rH3R Ki = 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 H3R 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.
