title: Synthesis of constrained benzocinnolinone analogues of CEP-26401 (irdabisant) as potent, selective histamine H3 receptor inverse agonists.
abstract: A novel class of benzocinnolinones analogs of irdabisant were designed and synthesized as histamine H3R antagonists/inverse agonists. Modifications to the pyridazinone portion of the core and linker led to the identification of molecules with excellent target potency and selectivity with improved rat pharmacokinetic properties and reduced potential hERG liabilities.
authors.affiliation: Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. kurtajosef@verizon.net
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Josef
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Lyons
authors.forename: Rita
authors.initials: R
authors.lastname: Raddatz
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hudkins
mesh_terms: D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000494:pharmacology; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000494:pharmacology; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D015394:Molecular Structure; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D017442:Histamine Agonists; D054828:Histamine H3 Antagonists; D018697:Nootropic Agents; D011724:Pyridazines; D011759:Pyrrolidines; D018100:Receptors, Histamine H3; C561238:6-(4-(3-(2-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-pyridazin-3-one