To optimize the lead urea scaffold 1 and 2 as selective cardiac myosin ATPase activator, a series of urea derivatives have been synthesized to explore its structure activity relationship. Among them N,N-dimethyl-4-(2-(3-(3-phenylpropyl)ureido)ethyl)benzenesulfonamide (13, CMA = 91.6%, FS = 17.62%; EF = 11.55%), N,N-dimethyl-4-(2-(1-methyl-3-(3-phenylpropyl)ureido)ethyl)benzene sulfonamide (40, CMA = 52.3%, FS = 38.96%; EF = 24.19%) and N,N-dimethyl-4-(2-(3-methyl-3-(3-phenylpropyl)ureido)ethyl)benzenesulfonamide (41, CMA = 47.6%, FS = 23.19%; EF = 15.47%) proved to be efficient to activate the cardiac myosin in vitro and in vivo. Further the % change in ventricular cell contractility at 5 μM of 13 (47.9 ± 3.2), 40 (45.5 ± 2.4) and 41 (63.5 ± 2.2) showed positive inotropic effect in isolated rat ventricular myocytes. The potent compounds 13, 40, 41 were highly selective for cardiac myosin over skeletal and smooth muscle myosin, thus proving them these new urea derivatives is a novel scaffold for discovery of cardiac myosin activators for the treatment of systolic heart failure.

为了优化尿素铅支架1和2作为选择性心肌肌球蛋白ATPase激活剂，已合成了一系列尿素衍生物以探索其结构活性关系。其中N，N-二甲基-4-（2-（3-（3-（3-苯基丙基）脲基）乙基）苯磺酰胺（13，CMA = 91.6％，FS = 17.62％; EF = 11.55％），N，N-二甲基-4-（2-（1-甲基-3-（3-苯基丙基）脲基）乙基）苯磺酰胺（40，CMA = 52.3％，FS = 38.96％; EF = 24.19％）和N，N-二甲基-4 -（2-（3-甲基-3-（3-苯基丙基）脲基）乙基）苯磺酰胺（41，CMA = 47.6％，FS = 23.19％; EF = 15.47％）被证明可在体外激活心肌肌球蛋白和体内。此外，在5μM的13（47.9±3.2），40（45.5±2.4）和41（63.5±2.2）的心室细胞收缩百分比变化在离体大鼠心室肌细胞中表现出正性肌力作用。的有效的化合物13，40，41是用于在骨骼和平滑肌肌球蛋白心肌肌球蛋白的高选择性，从而证明它们这些新的脲衍生物为心肌肌球蛋白的活化剂的发现为收缩期心脏衰竭的治疗的新型支架。