Design, Synthesis And Biological Activity Of The New Cardiac Myosin Agonist

Heart failure is the final destination of a variety of cardiovascular disease,which isharmful to human health and life. According to the epidemiological studies show thatcardiovascular disease has become the top three causes of death disease worldwide. Therefore,the study of heart failure drugs is particularly important. Currently, there are three mainanti-heart failure drugs: diuretics, neuroendocrine blockers and inotropic drugs. Traditionalinotropic drugs which are through the second messenger (cAMP) pathway, increase theintracellular calcium ion concentration to achieve the purpose of treatment of heart failure. Itmay cause many side effects, such as high heart rate, low blood pressure, more myocardialoxygen consumption, cardiac arrhythmia and so on.Developing the anti-heart failure drugs which have positive inotropic effect and low sideeffects, becaomes very important. Because cardiac myosin regulate the downstream target ofmyocardial contractility,and It can effectively increase myocardial contractility withoutaffecting intracellular calcium ion concentration.The novel inotropic drugs is expected tobecome a new hope to heart failure treatment.In this paper,AF-2012HF001and CK-1827452are both compounds which have clearcardiac myosin agonism.In order to get a conpound which has good activity,I havedesigned,synthesis and evaluated many counpounds by the two conpounds above.AF-2012HF001is obtained by high-throughput screening and its structure is divided intothree parts, namely isonicotinamide structure on the left, naphthalene ring structure on theright and the middle of the hydrazone structure.Now, I have got17new compounds byModification and replacement using Hydrazine reaction and Hydrazone reaction. By the sameway, I have got13new compounds witch is modified by the Naphthalene ring on the right.Also, by changing both sides of AF-2012HF001,I have got24new compounds. CK-1827452is developed by Cytokinesis which is reported into the two phase of clinical, and I have gotCK-1827452by improving the synthetic route reported using DIBALH reduction, votiveamination reaction and Urea reactor and so on.Without conflicting with the patent, I havemodified the pyridine ring structure, piperazine ring structure and the linkers. I have got26new conpounds by modification of the structure. All of these compounds have been identifiedby the NMR and the LC-MS.In the screening of pharmacological activity,I have investigated the effect of conpoundson heart failure in zebrafish by using the zebrafish model which is induced by terfenadine.Theinvestigation include the effect of hemodynamic parameters, pericardial edema and heart area.The results showed that the pyridine substituted hydrazone compounds I-A-3and I-A-4caneffectively increase the velocity of blood flow of heart failure and improve the sympotoms ofheart failure. They can be the forerunner and tools for new compounds with furtherdeveloping potential.