To identify novel potent cardiac myosin activator, a series of diphenylalkylisoxazol-5-amine compounds 4–7 have been synthesized and evaluated for cardiac myosin ATPase activation. Among the 37 compounds, 4a (CMA at 10 µM = 81.6%), 4w (CMA at 10 µM = 71.2%) and 6b (CMA at 10 µM = 67.4%) showed potent cardiac myosin activation at a single concentration of 10 µM. These results suggested that the introduction of the amino-isoxazole ring as a bioisostere for urea group is acceptable for the cardiac myosin activation. Additional structure–activity relationship (SAR) studies were conducted. Para substitution (-Cl, –OCH₃, -SO₂N(CH₃)₂) to the phenyl rings or replacement of a phenyl ring with a heterocycle (pyridine, piperidine and tetrahydropyran) appeared to attenuate cardiac myosin activation at 10 µM. Additional hydrogen bonding acceptor next to the amino group of the isoxazoles did not enhance the activity. The potent isoxazole compounds showed selectivity for cardiac myosin activation over skeletal and smooth muscle myosin, and therefore these potent and selective isoxazole compounds could be considered as a new series of cardiac myosin ATPase activators for the treatment of systolic heart failure.

为了鉴定新的有效心肌肌球蛋白的活化剂，一系列diphenylalkylisoxazol -5-胺化合物的4 - 7已被合成并评价心肌肌球蛋白ATP酶的活化。在这37种化合物中，4a（10 µM时的CMA = 81.6％），4w（10 µM时的CMA = 71.2％）和6b（10 µM的CMA = 67.4％）在单一浓度10 µM时显示出强力的心肌肌球蛋白活化作用。这些结果表明，引入氨基-异恶唑环作为尿素基团的生物等排体对于心脏肌球蛋白的活化是可接受的。进行了额外的构效关系（SAR）研究。对位取代（-Cl，-OCH ₃，-SO ₂ N（CH ₃）₂）苯环或用杂环（吡啶，哌啶和四氢吡喃）取代苯环似乎会减弱10 µM时的心肌肌球蛋白活化。异恶唑氨基旁边的其他氢键受体没有增强活性。有效的异恶唑化合物对骨骼肌和平滑肌肌球蛋白的心肌肌球蛋白活化具有选择性，因此这些有效的和选择性的异恶唑化合物可被视为治疗收缩性心力衰竭的一系列新的心脏肌球蛋白ATPase激活剂。