title: Pharmacophore-based search, synthesis, and biological evaluation of anthranilic amides as novel blockers of the Kv1.5 channel.
abstract: The search for novel, potent Kv1.5 blockers based on an anthranilic amide scaffold employing a pharmacophore-based virtual screening approach is described. The synthesis and structure-activity relationships (SAR) with respect to inhibition of the Kv1.5 channel are discussed. The most potent compounds display sub-micromolar inhibition of Kv1.5 and no significant effect on the HERG channel. In addition, good oral bioavailability is demonstrated for compound 3i in rats.
authors.affiliation: Aventis Pharma Deutschland GmbH, Medicinal Chemistry and DG Cardiovascular, D-65926 Frankfurt, Germany. stefan.peukert@aventis.com
authors.forename: Stefan
authors.initials: S
authors.lastname: Peukert
authors.forename: Joachim
authors.initials: J
authors.lastname: Brendel
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirard
authors.forename: Carsten
authors.initials: C
authors.lastname: Strübing
authors.forename: Heinz-Werner
authors.initials: HW
authors.lastname: Kleemann
authors.forename: Thomas
authors.initials: T
authors.lastname: Böhme
authors.forename: Horst
authors.initials: H
authors.lastname: Hemmerle
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D051666:Kv1.5 Potassium Channel; D008958:Models, Molecular; D026902:Potassium Channel Blockers / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000577:Amides; C496981:KCNA5 protein, human; C496983:Kcna5 protein, rat; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D062367:ortho-Aminobenzoates