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 μM = 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-phenylpropyl)-3-((tetrahydro-2H-pyran-4-yl)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.

中文翻译：

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探索柔性苯丙基脲支架作为新型心脏肌球蛋白激活剂治疗收缩性心力衰竭的方法。

已合成了一系列柔性尿素衍生物，并被证明可作为选择性心肌肌球蛋白ATPase激活剂。其中1-苯乙基-3-（3-苯基丙基）尿素（1，心肌肌球蛋白ATPase活化为10μM= 51.1％; FS = 18.90; EF = 12.15）和1-苄基-3-（3-苯基丙基）尿素（在图9中，心肌肌球蛋白ATPase活化= 53.3％； FS = 30.04； EF = 18.27）在体内外均显示出显着活性。具有四氢吡喃-4-基部分的苯环的变化，即1-（3-苯基丙基）-3-（（四氢-2H-吡喃-4-基）甲基）脲（14，心肌肌球蛋白ATPase的活化度= 81.4％ ； FS = 20.50； EF = 13.10）和吗啉部分，即1-（2-吗啉代乙基）-3-（3-苯丙基）脲（21，心肌肌球蛋白ATPase活化度= 44.0％； FS = 24.79； EF = 15.65 ），被证明可以有效激活心肌肌球蛋白。有效化合物1，9，发现14和21对心肌肌球蛋白的选择性高于骨骼肌和平滑肌球蛋白。因此，这些尿素衍生物是有效的支架，可发展成为用于治疗收缩性心力衰竭的新型心脏肌球蛋白活化剂。