Novel 5-cyclopropyl-1,4-benzodiazepin-2-ones as potent and selective IKs-blocking Class III antiarrhythmic agents

被引:15
作者
Butcher, JW [1 ]
Liverton, NJ
Claremon, DA
Freidinger, RM
Jurkiewicz, NK
Lynch, JJ
Salata, JJ
Wang, JX
Dieckhaus, CM
Slaughter, DE
Vyas, K
机构
[1] Merck Res Labs, Dept Med Chem, W Point, PA 19486 USA
[2] Merck Res Labs, Dept Pharmacol, W Point, PA 19486 USA
[3] Merck Res Labs, Dept Drug Metab, W Point, PA 19486 USA
关键词
D O I
10.1016/S0960-894X(03)00049-0
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Novel 5-cyclopropyl-1,4-benzodiazepin-2-ones having various N-1 substituents were identified as potent and selective blockers of the slowly activating cardiac delayed rectifier potassium current (I-Ks). Compound 11 is the most potent I-Ks channel blocker reported to date. (C) 2003 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:1165 / 1168
页数:4
相关论文
共 19 条
[1]   K(v)LQT1 and IsK (minK) proteins associate to form the I-Ks cardiac potassium current [J].
Barhanin, J ;
Lesage, F ;
Guillemare, E ;
Fink, M ;
Lazdunski, M ;
Romey, G .
NATURE, 1996, 384 (6604) :78-80
[2]   EFFECTS OF NEW AND POTENT METHANESULFONANILIDE CLASS-III ANTIARRHYTHMIC AGENTS ON MYOCARDIAL REFRACTORINESS AND CONTRACTILITY IN ISOLATED CARDIAC-MUSCLE [J].
BASKIN, EP ;
SERIK, CM ;
WALLACE, AA ;
BROOKES, LM ;
SELNICK, HG ;
CLAREMON, DA ;
LYNCH, JJ .
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 1991, 18 (03) :406-414
[3]  
BIGGER JT, 1996, GOODMAN GILMANS PHAR, P840
[4]   Inhibition of I-Ks in guinea pig cardiac myocytes and guinea pig I-sK channels by the chromanol 293B [J].
Busch, AE ;
Suessbrich, H ;
Waldegger, S ;
Sailer, E ;
Greger, R ;
Lang, HJ ;
Lang, F ;
Gibson, KJ ;
Maylie, JG .
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, 1996, 432 (06) :1094-1096
[5]   Preparation of 3-amino-1,4-benzodiazepin-2-ones via direct azidation with trisyl azide [J].
Butcher, JW ;
Liverton, NJ ;
Selnick, HG ;
Elliot, JM ;
Smith, GR ;
Tebben, AJ ;
Pribush, DA ;
Wai, JS ;
Claremon, DA .
TETRAHEDRON LETTERS, 1996, 37 (37) :6685-6688
[6]   USE-DEPENDENT EFFECTS OF THE CLASS-III ANTIARRHYTHMIC AGENT NE-10064 (AZIMILIDE) ON CARDIAC REPOLARIZATION - BLOCK OF DELAYED RECTIFIER POTASSIUM AND L-TYPE CALCIUM CURRENTS [J].
FERMINI, B ;
JURKIEWICZ, NK ;
JOW, B ;
GUINOSSO, PJ ;
BASKIN, EP ;
LYNCH, JJ ;
SALATA, JJ .
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 1995, 26 (02) :259-271
[7]   Synthesis and activity of novel and selective IKs-channel blockers [J].
Gerlach, U ;
Brendel, J ;
Lang, HJ ;
Paulus, EF ;
Weidmann, K ;
Brüggemann, A ;
Busch, AE ;
Suessbrich, H ;
Bleich, M ;
Greger, R .
JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (23) :3831-3837
[8]   IKs channel blockers:: potential antiarrhythmic agents [J].
Gerlach, U .
DRUGS OF THE FUTURE, 2001, 26 (05) :473-484
[9]   CLASS-III ANTIARRHYTHMIC AGENTS HAVE A LOT OF POTENTIAL BUT A LONG WAY TO GO - REDUCED EFFECTIVENESS AND DANGERS OF REVERSE USE DEPENDENCE [J].
HONDEGHEM, LM ;
SNYDERS, DJ .
CIRCULATION, 1990, 81 (02) :686-690
[10]  
HONDEGHEM LM, 1995, J CARDIOVASC PHA S4A, V20, P28