Optimization of tricyclic Nec-3 necroptosis inhibitors for in vitro liver microsomal stability



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Bioorganic and Medicinal Chemistry Letters


Necroptosis is a regulated caspase-independent cell death pathway with morphological features resembling passive non-regulated necrosis. Several diverse structure classes of necroptosis inhibitors have been reported to date, including a series of 3,3a,4,5-tetrahydro-2H-benz[g]indazoles (referred to as the Nec-3 series) displaying potent activity in cellular assays. However, evaluation of the tricyclic necroptosis inhibitor’s stability in mouse liver microsomes indicated that they were rapidly degraded. A structure–activity relationship (SAR) study of this compound series revealed that increased liver microsomal stability could be accomplished by modification of the pendent phenyl ring and by introduction of a hydrophilic substituent (i.e., ?-hydroxyl) to the acetamide at the 2-position of the tricyclic ring without significantly compromising necroptosis inhibitory activity. Further increases in microsomal stability could be achieved by utilizing the 5,5-dioxo-3-phenyl-2,3,3a,4-tetrahydro-[1]benzothiopyrano[4,3-c]pyrazoles. However, in this case necroptosis inhibitory activity was not maintained. Overall, these results provide a strategy for generating potent and metabolically stable tricyclic necrostatin analogs (e.g., 33, LDN-193191) potentially suitable for in vivo studies.



Nec-3, Necroptosis, Inhibitors, structure-activity relationship, microsomal stability


Copyright 2012 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/S0960894X1200858X. Recommended citation: Choi, Sungwoon, Heather Keys, Richard J. Staples, Junying Yuan, Alexei Degterev, and Gregory D. Cuny. "Optimization of tricyclic Nec-3 necroptosis inhibitors for in vitro liver microsomal stability." Bioorganic & medicinal chemistry letters 22, no. 17 (2012): 5685-5688. doi: 10.1016/j.bmcl.2012.06.098. This item has been deposited in accordance with publisher copyright and licensing terms and with the author's permission.