Design and synthesis of 4-substituted benzamides as potent, selective, and orally bioavailable I(Ks) blockers.
Multiple delayed rectifier potassium currents, including I(Ks), are responsible for the repolarization and termination of the cardiac action potential, and blockers of these currents may be useful as antiarrhythmic agents. Modification of compound 5 produced 19(S) that is the most potent I(Ks) blocker reported to date with >5000-fold selectivity over other cardiac ion channels. Further modification produced 24A with 23% oral bioavailability.
Lloyd
J
J
Schmidt
J B
JB
Rovnyak
G
G
Ahmad
S
S
Atwal
K S
KS
Bisaha
S N
SN
Doweyko
L M
LM
Stein
P D
PD
Traeger
S C
SC
Mathur
A
A
Conder
M L
ML
DiMarco
J
J
Harper
T W
TW
Jenkins-West
T
T
Levesque
P C
PC
Normandin
D E
DE
Russell
A D
AD
Serafino
R P
RP
Smith
M A
MA
Lodge
N J
NJ
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D015195:Drug Design; D066298:In Vitro Techniques; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D009865:Oocytes / Q000378:metabolism / Q000502:physiology; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; 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; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014981:Xenopus
C439948:3-butyl-5-(4-(((2,2-dimethylcyclopent-1-yl)methyl)aminocarbonyl)phenyl)-1,2,4-oxadiazole; D001549:Benzamides; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496911:Kcnq1 protein, rat; D010069:Oxadiazoles; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C059983:potassium channel protein I(sk)