Synthesis and evaluation of pyridone-phenoxypropyl-R-2-methylpyrrolidine analogues as histamine H3 receptor antagonists |
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Authors: | Becknell Nadine C Lyons Jacquelyn A Aimone Lisa D Gruner John A Mathiasen Joanne R Raddatz Rita Hudkins Robert L |
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Affiliation: | Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. nbecknell@cephalon.com |
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Abstract: | 6-{4-[3-(R)-2-Methylpyrrolidin-1-yl)propoxy]-phenyl}-2H-pyridazin-3-one 6 (Irdabisant; CEP-26401) was recently reported as a potent H(3)R antagonist with excellent drug-like properties and in vivo activity that advanced into clinical evaluation. A series of pyridone analogs of 6 was synthesized and evaluated as H(3)R antagonists. Structure-activity relationships revealed that the 5-pyridone regiomer was optimal for H(3)R affinity. N-Methyl 9b showed excellent H(3)R affinity, acceptable pharmacokinetics and pharmaceutical properties. In vivo evaluation of 9b showed potent activity in the rat dipsogenia model and robust wake-promoting activity in the rat EEG model. |
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Keywords: | Histamine H3 H3 Antagonists CEP-26401 Pyridone Sleep-wake |
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