Design And Synthesis Of Potent ROCK2 Isoform-Selective Inhibitors

ROCK has become one of the important target for the development of new drugs,which including two isoforms: ROCK1 and ROCK2.Despite the fact that they are highly homologous,accumulating evidence have showed that ROCK1 and ROCK2 have different biological functions.The development of highly potent and isoform selective ROCK2 inhibitors will pave new roads for treatment of a serious of diseases.While most currently reported available agents cannot target ROCK1 or ROCK2 isoform selectively.In this article,we have designed and synthesised a series of pyridyl-amide-chromans based on leading compound SR3677.Modifications on hinge region,side chains and hydrophobic region of SR3677 will lead us to identify highly potent and isoform selective pyridyl-amide-chroman based ROCK2 inhibitors.In the study of ROCK2/1 isoform selectivity,we have docked the candidate compounds to ROCK1 and ROCK2 proteins respectively to investigate the relationship between structure of the compound and its biological activity(or isoform selectivity).The results of molecular docking indicate that hydrophobic interactions formed in ROCK2 kinase play a key role in inhibit activity and isoform selectivity of candidate compounds.The reliability of docking results have verified by molecular simulations.In addition,the results of free energy calculations revealed that differences of van der waals(?Gvdw)interactions in(S)-7c-ROCK1 and(S)-7cROCK2 complexes may be a main reason for ROCK2 isoform selectivity.We also gained deep insight into the contribution of each residue by binding free energy decomposition analysis and identified the key reside Lys121 whcih play a key role in ROCK2 isoform selectivity.These results have theoretically revealed relationship between the structure of inhibitor and inhibition of ROCK2 activity and ROCK2/1 isoform selectivity.Meanwhile,we achieved the goal of furnishing the enantiomerically pure 6-methoxy-chroman-acids via recrystallization with multi-gram quantities of each chroman enantiomer.