Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late INai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties.
Late sodium current (late INa) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Nav1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late INa, is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia-ventricular fibrillation (VT-VF). We will describe structure-activity relationship (SAR) leading to the discovery of 4 that is vastly improved from the first generation late INainhibitor 1 (ranolazine). Compound 4 was 42 times more potent than 1 in reducing ischemic burden in vivo (S-T segment elevation, 15 min left anteriorior descending, LAD, occlusion in rabbits) with EC50values of 190 and 8000 nM, respectively. Compound 4 represents a new class of potent late INainhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients.
Jeff A
JA
Zablocki
Elfatih
E
Elzein
Xiaofen
X
Li
Dmitry O
DO
Koltun
Eric Q
EQ
Parkhill
Tetsuya
T
Kobayashi
Ruben
R
Martinez
Britton
B
Corkey
Haibo
H
Jiang
Thao
T
Perry
Rao
R
Kalla
Gregory T
GT
Notte
Oliver
O
Saunders
Michael
M
Graupe
Yafan
Y
Lu
Chandru
C
Venkataramani
Juan
J
Guerrero
Jason
J
Perry
Mark
M
Osier
Robert
R
Strickley
Biology, Gilead Sciences Inc. , 7601 Dumbarton Circle, Fremont, California 94555, United States.
Gongxin
G
Liu
Biology, Gilead Sciences Inc. , 7601 Dumbarton Circle, Fremont, California 94555, United States.
Wei-Qun
WQ
Wang
Biology, Gilead Sciences Inc. , 7601 Dumbarton Circle, Fremont, California 94555, United States.
Lufei
L
Hu
Biology, Gilead Sciences Inc. , 7601 Dumbarton Circle, Fremont, California 94555, United States.
Xiao-Jun
XJ
Li
Biology, Gilead Sciences Inc. , 7601 Dumbarton Circle, Fremont, California 94555, United States.
Nesrine
N
El-Bizri
Biology, Gilead Sciences Inc. , 7601 Dumbarton Circle, Fremont, California 94555, United States.
Ryoko
R
Hirakawa
Biology, Gilead Sciences Inc. , 7601 Dumbarton Circle, Fremont, California 94555, United States.
Kris
K
Kahlig
Biology, Gilead Sciences Inc. , 7601 Dumbarton Circle, Fremont, California 94555, United States.
Cheng
C
Xie
Biology, Gilead Sciences Inc. , 7601 Dumbarton Circle, Fremont, California 94555, United States.
Cindy Hong
CH
Li
Biology, Gilead Sciences Inc. , 7601 Dumbarton Circle, Fremont, California 94555, United States.
Arvinder K
AK
Dhalla
Biology, Gilead Sciences Inc. , 7601 Dumbarton Circle, Fremont, California 94555, United States.
Sridharan
S
Rajamani
Nevena
N
Mollova
Daniel
D
Soohoo
Eve-Irene
EI
Lepist
Bernard
B
Murray
Gerry
G
Rhodes
Biology, Gilead Sciences Inc. , 7601 Dumbarton Circle, Fremont, California 94555, United States.
Luiz
L
Belardinelli
Manoj C
MC
Desai