Design,Synthesis And Biological Evaluation Of Novel Selective ZAK Inhibitors

Hypertrophic cardiomyopathy?HCM?is the most common inherited cardiovascular disorder,which may result in sudden cardiac death,end-stage heart failure and stroke.Leucine-zipper and sterile-?motif kinase?ZAK?is a new potential targets for anti-hypertrophic cardiomyopathy?HCM?drug discovery.A series of 1,2,3-Triazole Benzenesulfonamides were designed and synthesized as new selective ZAK inhibitors.One of the most promising compounds,10e,tightly bound to ZAK with a Kd value of 8.0 nM,and potently inhibited the kinase activity of ZAK with an IC₅₀ value of 4.0 nM.Meanwhile,10e also exhabits good selectivity for 468 kinases?including 403 non-mutant kinases?.It can dose-dependently suppressed the activation of ZAK induced hypertrophy by blocking p38/GATA-4 and JNK/c-Jun signaling.Compound 10e also displayed reasonable pharmacokinetic properties and exhibited promising in vivo anti-HCM effect on spontaneous hypertensive rat?SHR?model.Compound 10e may serve as a lead compound for new anti-HCM drug discovery.