Development of novel cardiotonic agents

本研究旨在阐明新型强心剂的作用机制，为其临床应用提供基础资料。在所研究的新化合物中，Org 30029[N-羟基-5，6-二甲氧基苯并[b]噻吩甲酰亚胺盐酸盐]是最有效的正性变力作用(PIE)，这主要是由于提高了肌原纤维对钙离子的敏感性。由于这类药物(钙增敏剂)既不需要激活能，也不会导致钙超载，它们可能会为治疗心力衰竭患者提供有益的临床治疗方法。Org 30029的化学结构稍有改变，其增敏作用较弱，主要以PDE抑制为主，提示这些作用的部位可能具有密切相关的特征。获得的另一个结果与PDE III抑制剂在完整心肌中的作用机制有关。…进一步总结如下：1)参与哺乳动物心肌cAMP水解的PDE同工酶表现出广泛的物种依赖性变异；2)PDE抑制剂具有双重作用，即直接PIE和增强肾上腺素能受体激活PIE的作用。前者的作用比后者需要更高的浓度，这在这些药物的临床应用中具有重要意义；3)一些新的化合物，如维司力农和匹莫本丹，除了对PDE的抑制外，还具有辅助作用。由于这两种药物对严重心力衰竭患者的预后(存活率)都有有利的影响，因此区分哪些机制对临床有效性最重要是很重要的；4)虽然cAMP降低肌原纤维对肌钙蛋白I的磷酸化的敏感性，但PDE III抑制剂与β-激动剂相比没有产生这种作用，这意味着心肌细胞中cAMP的细胞内区隔。这种差异在临床环境下的病理生理学相关性目前尚不清楚，需要进一步研究。已经开发了几种新的药物，但到目前为止还没有药物可以取代洋地黄来治疗心力衰竭。将需要进一步的密集努力，包括通过仔细研究和合成具有新机制的新药物来评估这些药物的临床实用性。较少

The purpose of the study was to elucidate the mechanism of action of novel cardiotonic agents to provide basic information about useful for clinical application of these agents. Among new compounds investigated, Org 30029 [N-hydroxy-5,6-dimethoxybenzo [b] thiophene-2-carboximide hydrochloride] was the agent with most efficacious positive inotropic effect (PIE), which was mainly due to an increase in Ca^<2+> sensitivity of myofibrils. Because agents belonging to this class (Ca^<2+> sensitizer) neither require activation energy nor cause Ca^<2+> overload, they may provide beneficial clinical procedures to cure the patients with heart failure. Org 3731 with a slight modification of chemical structure of Org 30029 had much less Ca^<2+> sensitizing action and acted mainly by PDE inhibition, indicating that the site of these actions may possess a closely related characteristic. Another result obtained are concerned with the mechanism of action of PDE III inhibitors in intact cardiac muscle. … More These are summarized as follows : 1) PDE isozymes involved in cAMP hydrolysis in mammalian cardiac muscle show a wide range of species dependent variation ; 2) PDE inhibitors have a dual action, i.e., a direct PIE and the action to potentiate the PIE of adrenoceptor activation. The former action requires much higher concentration than the latter, which has a crucial meaning in clinical application of these agents ; 3) some novel compounds such as vesnarinone and pimobendan possess ancillary actions in addition to PDE inhibition. Since both agents have beneficial effects on the prognosis (survival rate) of the patients with severe heart failure, it is important to differentiate which mechanisms contribute most significantly to the clinical usefulness ; 4) while cAMP decreases the Ca^<2+> sensitivity of myofibrils in association with phosphorylation of troponin I,PDE III inhibitors did not produce such an action in contrast to beta- agonists, implying the intracellular compartmentation of cAMP in myocardial cells. Pathophysiological relevance of this difference under clinical setting is unknown for the time being and requires further study. Several novel agents have been developed, but there are no agents so far to replace digitalis in the treatment of heart failure. Further intensive effort will be required including evaluation of the clinical usefulness of these agents by careful investigation and synthesis of new agents with novel mechanism. Less