title: Novel heterocyclic-substituted benzofuran histamine H3 receptor antagonists: in vitro properties, drug-likeness, and behavioral activity.
abstract: Three novel heterocyclic benzofurans A-688057 (1), A-687136 (2), and A-698418 (3) were profiled for their in vitro and in vivo properties as a new series of histamine H(3) receptor antagonists. The compounds were all found to have nanomolar potency in vitro at histamine H(3) receptors, and when profiled in vivo for CNS activity, all were found active in an animal behavioral model of attention. The compound with the most benign profile versus CNS side effects was selected for greater scrutiny of its in vitro properties and overall drug-likeness. This compound, A-688057, in addition to its potent and robust efficacy in two rodent behavioral models at blood levels ranging 0.2-19 nM, possessed other favorable features, including high selectivity for H(3) receptors (H(3), K(i)=1.5 nM) versus off-target receptors and channels (including the hERG K(+) channel, K(i)>9000 nM), low molecular weight (295), high solubility, moderate lipophilicity (logD(pH7.4)=2.05), and good CNS penetration (blood/brain 3.4x). In vitro toxicological tests indicated low potential for phospholipidosis, genotoxicity, and CYP(450) inhibition. Even though pharmacokinetic testing uncovered only moderate to poor oral bioavailability in rat (26%), dog (30%), and monkey (8%), and only moderate blood half-lives after i.v. administration (t(1/2) in rat of 2.9h, 1.7h in dog, 1.8h in monkey), suggesting poor human pharmacokinetics, the data overall indicated that A-688057 has an excellent profile for use as a pharmacological tool compound.
authors: GPRD_AP9a/216, Department of Neuroscience Research, Abbott Laboratories, Abbott Park, IL 60064-6123, USA. marlon.d.cowart@abbott.com
authors: Marlon
authors: M
authors: Cowart
authors: Gregory A
authors: GA
authors: Gfesser
authors: Kaitlin E
authors: KE
authors: Browman
authors: Ramin
authors: R
authors: Faghih
authors: Thomas R
authors: TR
authors: Miller
authors: Ivan
authors: I
authors: Milicic
authors: John L
authors: JL
authors: Baranowski
authors: Kathleen M
authors: KM
authors: Krueger
authors: David G
authors: DG
authors: Witte
authors: Angela L
authors: AL
authors: Molesky
authors: Victoria A
authors: VA
authors: Komater
authors: Michael J
authors: MJ
authors: Buckley
authors: Gilbert J
authors: GJ
authors: Diaz
authors: Gerard D
authors: GD
authors: Gagne
authors: Deliang
authors: D
authors: Zhou
authors: Xiaoqing
authors: X
authors: Deng
authors: Liping
authors: L
authors: Pan
authors: Ellen M
authors: EM
authors: Roberts
authors: Marilyn S
authors: MS
authors: Diehl
authors: Jill M
authors: JM
authors: Wetter
authors: Kennan C
authors: KC
authors: Marsh
authors: Gerard B
authors: GB
authors: Fox
authors: Jorge D
authors: JD
authors: Brioni
authors: Timothy A
authors: TA
authors: Esbenshade
authors: Arthur A
authors: AA
authors: Hancock
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D000882:Haplorhini; D006633:Histamine Antagonists / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects / Q000502:physiology*
chemical_list: D001572:Benzofurans; D006633:Histamine Antagonists; D018100:Receptors, Histamine H3; C105430:benzofuran