Tetrahydronaphthalene-derived amino alcohols and amino ketones as potent and selective inhibitors of the delayed rectifier potassium current IKs.
Class III anti-arrhythmic drugs (e.g., dofetilide) prolong cardiac action potential duration (APD) by blocking the fast component of the delayed rectifier potassium current (I(Kr)). The block of I(Kr) can result in life threatening ventricular arrhythmias (i.e., torsades de pointes). Unlike I(Kr), the role of the slow component of the delayed rectifier potassium current (I(Ks)) becomes significant only at faster heart rate. Therefore selective blockers of I(Ks) could prolong APD with a reduced propensity to cause pro-arrhythmic side effects. This report describes structure-activity relationships (SARs) of a series of I(Ks) inhibitors derived from 6-alkoxytetralones with good in vitro activity (IC(50) > or =30 nM) and up to 40-fold I(Ks)/I(Kr) selectivity.
Ahmad
Saleem
S
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543, USA. saleem.ahmad@bms.com
Doweyko
Lidia
L
Ashfaq
Aaila
A
Ferrara
Francis N
FN
Bisaha
Sharon N
SN
Schmidt
Joan B
JB
DiMarco
John
J
Conder
Mary Lee
ML
Jenkins-West
Tonya
T
Normandin
Diane E
DE
Russell
Anita D
AD
Smith
Mark A
MA
Levesque
Paul C
PC
Lodge
Nicholas J
NJ
Lloyd
John
J
Stein
Philip D
PD
Atwal
Karnail S
KS
D000605:Amino Alcohols / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D051668:Delayed Rectifier Potassium Channels; D006168:Guinea Pigs; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D015221:Potassium Channels / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000494:pharmacology*
D000605:Amino Alcohols; D051668:Delayed Rectifier Potassium Channels; D007659:Ketones; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013764:Tetrahydronaphthalenes