Pharmacophore-based search, synthesis, and biological evaluation of anthranilic amides as novel blockers of the Kv1.5 channel.
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.
Peukert
Stefan
S
Aventis Pharma Deutschland GmbH, Medicinal Chemistry and DG Cardiovascular, D-65926 Frankfurt, Germany. stefan.peukert@aventis.com
Brendel
Joachim
J
Pirard
Bernard
B
Strübing
Carsten
C
Kleemann
Heinz-Werner
HW
Böhme
Thomas
T
Hemmerle
Horst
H
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
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