title: 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.
abstract: 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.
authors: Discovery and Product Development, Teva Pharmaceutical Global R&D, 145 Brandywine Parkway, West Chester, PA 19380, USA. Electronic address: robert.hudkins@tevapharm.com.
authors: Robert L
authors: RL
authors: Hudkins
authors: Discovery and Product Development, Teva Pharmaceutical Global R&D, 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Kurt A
authors: KA
authors: Josef
authors: Discovery and Product Development, Teva Pharmaceutical Global R&D, 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Nadine C
authors: NC
authors: Becknell
authors: Discovery and Product Development, Teva Pharmaceutical Global R&D, 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Lisa D
authors: LD
authors: Aimone
authors: Discovery and Product Development, Teva Pharmaceutical Global R&D, 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Jacquelyn A
authors: JA
authors: Lyons
authors: Discovery and Product Development, Teva Pharmaceutical Global R&D, 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Joanne R
authors: JR
authors: Mathiasen
authors: Discovery and Product Development, Teva Pharmaceutical Global R&D, 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: John A
authors: JA
authors: Gruner
authors: Discovery and Product Development, Teva Pharmaceutical Global R&D, 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Rita
authors: R
authors: Raddatz
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D054314:Drug Inverse Agonism; D006207:Half-Life; D000882:Haplorhini; D008570:Memory, Short-Term / Q000187:drug effects; D018697:Nootropic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011724:Pyridazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C573777:4,5-dihydropyridazin-3-one; C000592652:5-(4-(1-cyclobutylpiperidin-4-yloxy)phenyl)-3,4-diazabicyclo(4.1.0)hept-4-en-2-one; D018697:Nootropic Agents; D010880:Piperidines; D011724:Pyridazines; D018100:Receptors, Histamine H3
keywords: CEP-26401; Cognition; H(3) inverse agonist; Histamine H(3) receptor; Pyridazin-3-one; Sleep–wake