Journal article
Optimization of 5-Pyridazin-3-one Phenoxypropylamines as Potent, Selective Histamine H-3 Receptor Antagonists with Potent Cognition Enhancing Activity
Journal of medicinal chemistry, v 55(1), pp 414-423
12 Jan 2012
PMID: 22107017
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 (hH3R K-i = 1.7 nM, rH(3)R K = 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.
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Details
- Title
- Optimization of 5-Pyridazin-3-one Phenoxypropylamines as Potent, Selective Histamine H-3 Receptor Antagonists with Potent Cognition Enhancing Activity
- Creators
- Ming Tao - Cephalon Inc, Discovery Res, W Chester, PA 19380 USALisa D. Aimone - Cephalon Inc, Discovery Res, W Chester, PA 19380 USAZeqi Huang - Cephalon Inc, Discovery Res, W Chester, PA 19380 USAJoanne Mathiasen - Cephalon Inc, Discovery Res, W Chester, PA 19380 USARita Raddatz - Cephalon Inc, Discovery Res, W Chester, PA 19380 USAJacquelyn Lyons - Cephalon Inc, Discovery Res, W Chester, PA 19380 USARobert L. Hudkins - Cephalon Inc, Discovery Res, W Chester, PA 19380 USA
- Publication Details
- Journal of medicinal chemistry, v 55(1), pp 414-423
- Publisher
- Amer Chemical Soc
- Number of pages
- 10
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000298978800032
- Scopus ID
- 2-s2.0-84855845974
- Other Identifier
- 991021900015904721
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InCites Highlights
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- Web of Science research areas
- Chemistry, Medicinal