Potassium channel blocking 1,2-bis(aryl)ethane-1,2-diamines active as antiarrhythmic agents

被引：6

作者：

Kajanus, Johan ^{[1
]}

Antonsson, Thomas ^{[1
]}

Carlsson, Leif ^{[1
]}

Jurva, Ulrik ^{[1
]}

Pettersen, Anna ^{[2
]}

Sundell, Johan ^{[1
]}

Inghardt, Tord ^{[1
]}

机构：

[1] AstraZeneca, IMED Biotech Unit, Cardiovasc Renal & Metab, Gothenburg, Sweden

[2] AstraZeneca, IMED Biotech Unit, Pharmaceut Sci, Gothenburg, Sweden

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2019年 / 29卷 / 10期

关键词：

Kv1.5; IKur; Atrial fibrillation; Antiarrhythmic agents; Potassium channel blocker; 1,2-bis(aryl)ethane-1,2-diamines; ATRIAL-FIBRILLATION; POTENT INHIBITORS; IN-VITRO; DISCOVERY; TARGETS; AMIDES;

D O I：

10.1016/j.bmcl.2019.03.006

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Atrial fibrillation (AF) is a major cause of stroke, heart failure, sudden death and cardiovascular morbidity. The Kv1.5 potassium channel conducts the IKur current and has been demonstrated to be predominantly expressed in atrial versus ventricular tissue. Blockade of Kv1.5 has been proven to be an effective approach to restoring and maintaining sinus rhythm in preclinical models of AF. In the clinical setting, however, the therapeutic value of this approach remains an open question. Herein, we present synthesis and optimization of a novel series of 1,2-bis(aryl)ethane-1,2-diamines with selectivity for Kv1.5 over other potassium ion channels. The effective refractory period in the right atrium (RAERP) in a rabbit PD model was investigated for a selection of potent and selective compounds with balanced DMPK properties. The most advanced compound (10) showed nanomolar potency in blocking Kv1.5 in human atrial myocytes and based on the PD data, the estimated dose to man is 700 mg/day. As previously reported, 10 efficiently converted AF to sinus rhythm in a dog disease model.

引用

页码：1241 / 1245

页数：5