Structure–activity relationship and liver microsome stability studies of pyrrole necroptosis inhibitors



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Bioorganic and Medicinal Chemistry Letters


Necroptosis is a regulated caspase-independent cell death pathway resulting in morphology reminiscent of passive non-regulated necrosis. Several diverse structure classes of necroptosis inhibitors have been reported to date, including a series of [1,2,3]thiadiazole benzylamide derivatives. However, initial evaluation of mouse liver microsome stability indicated that this series of compounds was rapidly degraded. A structure–activity relationship (SAR) study of the [1,2,3]thiadiazole benzylamide series revealed that increased mouse liver microsome stability and increased necroptosis inhibitory activity could be accomplished by replacement of the 4-cyclopropyl-[1,2,3]thiadiazole with a 5-cyano-1-methylpyrrole. In addition, the SAR and the cellular activity profiles, utilizing different cell types and necroptosis-inducing stimuli, of representative [1,2,3]thiadiazole and pyrrole derivatives were very similar suggesting that the two compound series inhibit necroptosis in the same manner.



Cell death, Necrosis, Necroptosis, Microsome stability, Caspase-independent, Pyrroles, SAR


Copyright 2008 Bioorganic and Medicinal Chemistry Letters. This is is a post-print version of a published paper that is available at: citation: Teng, Xin, Heather Keys, Junying Yuan, Alexei Degterev, and Gregory D. Cuny. "Structure–activity relationship and liver microsome stability studies of pyrrole necroptosis inhibitors." Bioorganic & medicinal chemistry letters 18, no. 11 (2008): 3219-3223. doi: 10.1016/j.bmcl.2008.04.048. This item has been deposited in accordance with publisher copyright and licensing terms and with the author's permission.