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

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• 作者：Ming Tao ; Lisa D. Aimone ; Zeqi Huang ; Joanne Mathiasen ; Rita Raddatz ; Jacquelyn Lyons ; Robert L. Hudkins
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：January 12, 2012
• 年：2012
• 卷：55
• 期：1
• 页码：414-423
• 全文大小：314K
• 年卷期：v.55,no.1(January 12, 2012)
• ISSN：1520-4804

文摘

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 K_i = 2.8 nM) and rat H₃Rs (rH₃R K_i = 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 K_i = 1.7 nM, rH₃R 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 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.