title: Identification, synthesis, and activity of novel blockers of the voltage-gated potassium channel Kv1.5.
abstract: The voltage-gated potassium channel Kv1.5 is regarded as a promising target for the development of new atrial selective drugs with fewer side effects. In the present study the discovery of ortho,ortho-disubstituted bisaryl compounds as blockers of the Kv1.5 channel is presented. Several compounds of this new class were synthesized and screened for their ability to block Kv1.5 channels expressed in Xenopus oocytes. The observed structure-activity relationship (SAR) is described by a pharmacophore model that consists of three hydrophobic centers in a triangular arrangement. The hydrophobic centers are matched by a phenyl or pyridyl ring of the bisaryl core and both ends of the side chains. The most potent compounds (e.g., 17c and 17o) inhibited the Kv1.5 channel with sub-micromolar half-blocking concentrations and displayed 3-fold selectivity over Kv1.3 and no significant effect on the HERG channel and sodium currents. In addition, compounds 17c and 17m have already shown antiarrhythmic effects in a pig model.
authors.affiliation: Aventis Pharma Deutschland GmbH, Medicinal Chemistry and DG Cardiovascular, D-65926 Frankfurt/Main, Germany. stefan.peukert@aaventis.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: Andrea
authors.initials: A
authors.lastname: Brüggemann
authors.forename: Peter
authors.initials: P
authors.lastname: Below
authors.forename: Heinz-Werner
authors.initials: HW
authors.lastname: Kleemann
authors.forename: Horst
authors.initials: H
authors.lastname: Hemmerle
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D051666:Kv1.5 Potassium Channel; D008958:Models, Molecular; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D000889:Anti-Arrhythmia Agents; D001713:Biphenyl Compounds; C496981:KCNA5 protein, human; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines