Teng, XinKeys, HeatherJeevanandam, ArumugasamyPorco, John A. Jr.Degterev, AlexeiYuan, JunyingCuny, Gregory D.2020-03-102020-03-102008-12Copyright 2007 Bioorganic and Medicinal Chemistry Letters. This is a post-print version of a published paper that is available at: https://www.sciencedirect.com/science/article/pii/S0960894X07011882. Recommended Citation: Teng, Xin, Heather Keys, Arumugasamy Jeevanandam, John A. Porco Jr, Alexei Degterev, Junying Yuan, and Gregory D. Cuny. "Structure–activity relationship study of [1, 2, 3] thiadiazole necroptosis inhibitors." Bioorganic & medicinal chemistry letters 17, no. 24 (2007): 6836-6840. doi:10.1016/j.bmcl.2007.10.024. This item has been deposited in accordance with publisher copyright and licensing terms and with the author's permission.https://hdl.handle.net/10657/5982Necroptosis is a regulated caspase-independent cell death mechanism that results in morphological features resembling non-regulated necrosis. This form of cell death can be induced in an array of cell types in apoptotic deficient conditions with death receptor family ligands. A series of [1,2,3]thiadiazole benzylamides was found to be potent necroptosis inhibitors (called necrostatins). A structure activity relationship study revealed that small cyclic alkyl groups (i.e. cyclopropyl) and 2,6-dihalobenzylamides at the 4- and 5-positions of the [1,2,3]thiadiazole, respectively, were optimal. In addition, when a small alkyl group (i.e. methyl) was present on the benzylic position all the necroptosis inhibitory activity resided with the (S)-enantiomer. Finally, replacement of the [1,2,3]thiadiazole with a variety of thiophene derivatives was tolerated, although some erosion of potency was observed.en-USNecroptosisCell deathCaspase-independentNecrosis[1,2,3]ThiadiazoleArticle