title: 4-[6-(2-Aminoethyl)naphthalen-2-yl]benzonitriles are potent histamine H3 receptor antagonists with high CNS penetration.
abstract: 4-[6-(2-Tertiaryaminoethyl)naphthalen-2-yl]benzonitriles are conformationally constrained histamine H3 receptor antagonists with high potency and selectivity. The analogs were designed around a naphthalene core, with the goal of enhancing lipophilicity and CNS penetration, as compared to a previously reported benzofuran series. The SAR of the tertiary amine moiety is similar to that reported for the benzofuran series, with analogs bearing a 2-methylpyrrolidine substituent possessing the greatest rat and human H3 receptor binding affinities.
authors.affiliation: Neuroscience Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USA. larry.a.black@abbott.com
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Black
authors.forename: Diana L
authors.initials: DL
authors.lastname: Nersesian
authors.forename: Padam
authors.initials: P
authors.lastname: Sharma
authors.forename: Yi-Yin
authors.initials: YY
authors.lastname: Ku
authors.forename: Youssef L
authors.initials: YL
authors.lastname: Bennani
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Miller
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Esbenshade
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Hancock
authors.forename: Marlon
authors.initials: M
authors.lastname: Cowart
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism*; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009281:Naphthalenes; D009570:Nitriles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D010539:Permeability; D011485:Protein Binding; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D006633:Histamine Antagonists; D009281:Naphthalenes; D009570:Nitriles; D018100:Receptors, Histamine H3; C031721:naphthalene; C014356:benzonitrile