Browsing by Author "Staples, Richard J."
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Item Optimization of tricyclic Nec-3 necroptosis inhibitors for in vitro liver microsomal stability(Bioorganic and Medicinal Chemistry Letters, 2013-09) Choi, Sungwoon; Keys, Heather; Staples, Richard J.; Yuan, Junying; Degterev, Alexei; Cuny, Gregory D.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.Item (S)-N-(1-Phenylethylpiperidin-1-ium-3-ylmethyl)- N-phenylpropionamide trifluoroacetate(Acta Crystallographica, 2003-08) Shao, Liming; Cuny, Gregory D.; Hauske, James R.; Staples, Richard J.