Exploration of flexible phenylpropylurea scaffold as novel cardiac myosin activators for the treatment of systolic heart failure

被引：12

作者：

Manickam, Manoj ^{[1
]}

Jalani, Hitesh B. ^{[1
]}

Pillaiyar, Thanigaimalai ^{[1
]}

Sharma, Niti ^{[1
]}

Boggu, Pulla Reddy ^{[1
]}

Venkateswararao, Eeda ^{[1
]}

Lee, You-Jung ^{[2
]}

Jeon, Eun-Seok ^{[2
]}

Jung, Sang-Hun ^{[1
]}

机构：

[1] Chungnam Natl Univ, Inst Drug Res & Dev, Coll Pharm, Daejeon 34134, South Korea

[2] Sungkyunkwan Univ, Div Cardiol, Samsung Med Ctr, Samsung Biomed Res Inst,Sch Med, 81 Irwon Ro, Seoul 06351, South Korea

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 134卷

基金：

新加坡国家研究基金会;

关键词：

Flexible urea; Cardiac myosin activator; Inotrope; Systolic heart failure; OMECAMTIV-MECARBIL; GLOBAL BURDEN; MUSCLE MYOSIN; RECEPTOR; PHOSPHORYLATION; LEVOSIMENDAN; FLEXIBILITY; INHIBITORS; INOTROPES; MORTALITY;

D O I：

10.1016/j.ejmech.2017.04.005

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of flexible urea derivatives have been synthesized and demonstrated as selective cardiac myosin ATPase activator. Among them 1-phenethyl-3-(3-phenylpropyl)urea (1, cardiac myosin ATPase activation at 10) mu M = 51.1%; FS = 18.90; EF = 12.15) and 1-benzyl-3-(3-phenylpropyl)urea (9, cardiac myosin ATPase activation = 53.3%; FS = 30.04; EF = 18.27) showed significant activity in vitro and in vivo. The change of phenyl ring with tetrahydropyran-4-yl moiety viz., 1-(3-phenylpropy1)-3-((tetrahydro-2H-pyran-4-y1) methyl)urea (14, cardiac myosin ATPase activation = 81.4%; FS = 20.50; EF = 13.10), and morpholine moiety viz., 1-(2-morpholinoethyl)-3-(3-phenylpropyl)urea (21, cardiac myosin ATPase activation = 44.0%; FS = 24.79; EF = 15.65), proved to be efficient to activate the cardiac myosin. The potent compounds 1, 9, 14 and 21 were found to be selective for cardiac myosin over skeletal and smooth myosins. Thus, these urea derivatives are potent scaffold to develop as a newer cardiac myosin activator for the treatment of systolic heart failure. (C) 2017 Elsevier Masson SAS. All rights reserved.

引用

页码：379 / 391

页数：13

共 40 条

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