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Synthesis and evaluation of pyridazinone-phenethylamine derivatives as selective and orally bioavailable histamine H3 receptor antagonists with robust wake-promoting activity |
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| Authors: | Dandu Reddeppa Reddy Gruner John A Mathiasen Joanne R Aimone Lisa D Hostetler Greg Benfield Caitlyn Bendesky Robert J Marcy Val R Raddatz Rita Hudkins Robert L |
| Affiliation: | Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. rdandu@cephalon.com |
| Abstract: | A series of pyridazinone-phenethylamine derivatives with moderate to low nanomolar affinity for rat and human H(3)R are described. These analogs exhibited excellent selectivity and metabolic stability, with acceptable rat pharmacokinetic properties. In vivo, 7 and 11 demonstrated potent H(3)R functional antagonism in the rat dipsogenia model and robust wake-promoting activity in the rat electroencephalogram/electromyography (EEG/EMG) model. |
| Keywords: | H3R antagonists Pyridazinone (R)-2-Methylpyrrolidine H3 receptor Metabolic stability |
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