Discovery of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a): histamine H(3) receptor inverse agonist demonstrating potent cognitive enhancing and wake promoting activity.
A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one) phenoxypiperidine analogs was designed and synthesized, leading to the identification of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a) as a second-generation pyridazin-3-one H3R antagonist. Compound R,S-4a was a potent H3R functional antagonist in vivo in the rat dipsogenia model, demonstrated potent wake activity in the rat EEG/EMG model, and enhanced short-term memory in the rat social recognition memory model at doses as low as 0.03-0.3 mg/kg po.
['Hudkins|Robert L|RL|', 'Josef|Kurt A|KA|', 'Becknell|Nadine C|NC|', 'Aimone|Lisa D|LD|', 'Lyons|Jacquelyn A|JA|', 'Mathiasen|Joanne R|JR|', 'Gruner|John A|JA|', 'Raddatz|Rita|R|']
D000818:Animals D003072:Cognition Disorders D004195:Disease Models, Animal D004285:Dogs D004353:Drug Evaluation, Preclinical D054314:Drug Inverse Agonism D006207:Half-Life D000882:Haplorhini D008570:Memory, Short-Term D018697:Nootropic Agents D010880:Piperidines D011724:Pyridazines D051381:Rats D018100:Receptors, Histamine H3 D013237:Stereoisomerism D013329:Structure-Activity Relationship
Histamine H(3) receptor Cognition Pyridazin-3-one CEP-26401 H(3) inverse agonist Sleep–wake