Synthesis and evaluation of pyridone-phenoxypropyl-R-2-methylpyrrolidine analogues as histamine H3 receptor antagonists

6-{4-[3-(R)-2-Methylpyrrolidin-1-yl)propoxy]-phenyl}-2H-pyridazin-3-one 6 (Irdabisant; CEP-26401) was recently reported as a potent H3R 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 H3R antagonists. Structure–activity relationships revealed that the 5-pyridone regiomer was optimal for H3R affinity. N-Methyl 9b showed excellent H3R 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.

Compound 9b-induced wake promotion; cumulative wake 4 h AUC values shown for each dose (mean + SEM, n = 8, 5, and 10 for vehicle, 10, and 30 mg/kg groups). Compound administered ip to rats with chronically implanted electrodes for recording EEG and EMG activity. ∗p < 0.05 Dunnett’s post hoc versus vehicle.Figure optionsDownload as PowerPoint slide