title: Synthesis and activity of novel and selective I(Ks)-channel blockers.
abstract: Since the discovery of the I(Ks)-potassium channel as the slowly activating component of the delayed rectifier current (I(k)) in cardiac tissue, the search for blockers of this current has been intense. During the screening of K(ATP)-channel openers of the chromanol type we found that chromanol 293B was able to block I(Ks). Chromanol 293B is a sulfonamide analogue of the K(ATP)-channel openers but had no activity on this target. Experiments were initiated to improve the activity and properties based on this lead compound. As a screening model we used Xenopus oocytes injected with human minK (KCNE1). Variations of the aromatic substituent and the sulfonamide group were prepared, and their activity was evaluated. We found that the greatest influence on activity was found in the aromatic substituents. The most active compounds were alkoxy substituted. We chose HMR1556 ((3R, 4S)-(+)-N-[-3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methyl-ethanesulfonamide) 10a for development as an antiarrhythmic drug. The absolute configuration, resulting from an X-ray single-crystal structure analysis, was determined.
authors.affiliation: Aventis Pharma Deutschland GmbH, Medicinal Chemistry, DG Cardiovascular D-65926 Frankfurt/Main, Germany. uwe.Gerlach@aventis.com
authors.forename: U
authors.initials: U
authors.lastname: Gerlach
authors.forename: J
authors.initials: J
authors.lastname: Brendel
authors.forename: H J
authors.initials: HJ
authors.lastname: Lang
authors.forename: E F
authors.initials: EF
authors.lastname: Paulus
authors.forename: K
authors.initials: K
authors.lastname: Weidmann
authors.forename: A
authors.initials: A
authors.lastname: Brüggemann
authors.forename: A E
authors.initials: AE
authors.lastname: Busch
authors.forename: H
authors.initials: H
authors.lastname: Suessbrich
authors.forename: M
authors.initials: M
authors.lastname: Bleich
authors.forename: R
authors.initials: R
authors.lastname: Greger
mesh_terms: D000818:Animals; D002839:Chromans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006801:Humans; D066298:In Vitro Techniques; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D002839:Chromans; C420023:HMR 1556; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; C059983:potassium channel protein I(sk)