There is considerable interest both in industry and academia for the usefulness of histamine H3 receptor antagonist as a potential target for the treatments of several CNS disorders including Alzheimer's disease, schizophrenia, ADHD, obesity and narcolepsy. Herein we report our initial findings towards identification and pharmacological profiling of fused thiazolo tetrahydropyridinyl amides as novel, potent (hH3 Ki = 1 to 10 nM), and selective (>100 fold) H3 receptor antagonists. The lead compound blocked R-a-methylhistamine-induced water intake, suggesting that it behaves as a functional antagonist. The series in general have favorable pharmacokinetic properties, good oral bioavailability, no CYP liability and excellent brain penetration. The lead compound is orally active in preclinical model of cognition (NORT and Morris water maze), showed excellent receptor occupancy and activity in microdialysis assay at lower doses. The design, synthesis, SAR and pharmacological profile of these new analogs as potential treatments for cognitive dysfunction will be presented.

Fused thiazolo tetrahydropyridinyl amides as potent and selective histamine H<sub>3</sub> receptor antagonists

241st National Meeting (2011)

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Fused thiazolo tetrahydropyridinyl amides as potent and selective histamine H3 receptor antagonists

Fused thiazolo tetrahydropyridinyl amides as potent and selective histamine H₃ receptor antagonists