title: Synthesis, potency, and in vivo profiles of quinoline containing histamine H3 receptor inverse agonists.
abstract: A new structural series of histamine H3 receptor antagonist was developed. The new compounds are based on a quinoline core, appended with a required basic aminoethyl moiety, and with potency- and property-modulating heterocyclic substituents. The analogs have nanomolar and subnanomolar potency for the rat and human H3R in various in vitro assays, including radioligand competition binding as well as functional tests of H3 receptor-mediated calcium mobilization and GTPgammaS binding. The compounds possessed favorable drug-like properties, such as good PK, CNS penetration, and moderate protein binding across species. Several compounds were found to be efficacious in animal behavioral models of cognition and attention. Further studies on the pharmaceutic properties of this series of quinolines discovered a potential problem with photochemical instability, an issue which contributed to the discontinuation of this series from further development.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6123, USA. robert.j.altenbach@abbott.com
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Altenbach
authors.forename: Huaqing
authors.initials: H
authors.lastname: Liu
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Banfor
authors.forename: Kaitlin E
authors.initials: KE
authors.lastname: Browman
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Fox
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Fryer
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Komater
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Krueger
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Miller
authors.forename: Jia Bao
authors.initials: JB
authors.lastname: Pan
authors.forename: Liping
authors.initials: L
authors.lastname: Pan
authors.forename: Minghua
authors.initials: M
authors.lastname: Sun
authors.forename: Christine
authors.initials: C
authors.lastname: Thiffault
authors.forename: Jill
authors.initials: J
authors.lastname: Wetter
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.forename: Deliang
authors.initials: D
authors.lastname: Zhou
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Esbenshade
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Hancock
authors.forename: Marlon D
authors.initials: MD
authors.lastname: Cowart
mesh_terms: D000818:Animals; D001288:Attention / Q000187:drug effects; D001362:Avoidance Learning / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003071:Cognition / Q000187:drug effects; D004285:Dogs; D054314:Drug Inverse Agonism; D004355:Drug Stability; D000882:Haplorhini; D006801:Humans; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects; D012919:Social Behavior; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: C524712:2-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(2-(2-methylpyrrolidin-1-yl)ethyl)quinoline; C524711:2-(2,7-dimethylpyrazolo(1,5-a)pyrimidin-6-yl)-6-(2-(2-methylpyrrolidin-1-yl)ethyl)quinoline; D001798:Blood Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D011804:Quinolines; D018100:Receptors, Histamine H3; D002118:Calcium