Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA.
Bioorg Med Chem Lett. 2012 Sep 1;22(17):5685-8. doi: 10.1016/j.bmcl.2012.06.098. Epub 2012 Jul 6.
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., α-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.
细胞坏死是一种受调控的、不依赖半胱天冬酶的细胞死亡途径，其形态特征类似于无调控的被动坏死。迄今为止，已经报道了多种不同结构类型的细胞坏死抑制剂，包括一系列 3,3a,4,5-四氢-2H-苯并[g]吲哚（称为 Nec-3 系列），在细胞测定中显示出很强的活性。然而，对三环细胞坏死抑制剂在小鼠肝微粒体中的稳定性评估表明，它们会迅速降解。对该化合物系列的构效关系（SAR）研究表明，通过修饰悬垂的苯基环并在三环环的 2 位引入亲水性取代基（即α-羟基），可以实现肝微粒体稳定性的提高，而不会显著降低细胞坏死抑制活性。通过利用 5,5-二氧代-3-苯基-2,3,3a,4-四氢-[1]苯并噻吩并[4,3-c]吡唑，可以进一步提高微粒体稳定性。然而，在这种情况下，细胞坏死抑制活性无法维持。总的来说，这些结果提供了一种生成有效且代谢稳定的三环坏死抑制剂类似物（例如 33、LDN-193191）的策略，这些类似物可能适合进行体内研究。
