Synthesis and evaluation of pyridazinone–phenethylamine derivatives as selective and orally bioavailable histamine H₃ receptor antagonists with robust wake-promoting activity

A series of pyridazinone–phenethylamine derivatives with moderate to low nanomolar affinity for rat and human H₃R are described. These analogs exhibited excellent selectivity and metabolic stability, with acceptable rat pharmacokinetic properties. In vivo, 7 and 11 demonstrated potent H₃R functional...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2011-11, Vol.21 (21), p.6362-6365
Hauptverfasser:	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
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals antagonists Biological and medical sciences Biological Availability chemistry Electroencephalography Electromyography General aspects histamine Histamine H3 Antagonists - chemical synthesis Histamine H3 Antagonists - pharmacokinetics Histamine H3 Antagonists - pharmacology Humans Medical sciences Neuropharmacology pharmacokinetics Pharmacology. Drug treatments Rats Structure-Activity Relationship
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Zusammenfassung:	A series of pyridazinone–phenethylamine derivatives with moderate to low nanomolar affinity for rat and human H₃R are described. These analogs exhibited excellent selectivity and metabolic stability, with acceptable rat pharmacokinetic properties. In vivo, 7 and 11 demonstrated potent H₃R functional antagonism in the rat dipsogenia model and robust wake-promoting activity in the rat electroencephalogram/electromyography (EEG/EMG) model.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.08.104