Abstract An initial structure–activity relationship study of the novel necroptosis inhibitor Nec- 21 was described. Any changes of the tetracyclic scaffold were detrimental for the activity. Introduction of a substituent to 7 or 8 position (eg, cyano or methoxy group, respectively), would increase the activity. The 7 and 8-position disubstituted compound 17b was 35-fold as potent as the lead, while EC 50 reached 14 nM.
