Optimization of tricyclic Nec-3 necroptosis inhibitors for in vitro liver microsomal stability.
Optimization of tricyclic Nec-3 necroptosis inhibitors for in vitro liver microsomal stability.
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DOI：
10.1016/j.bmcl.2012.06.098
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发表时间：
2012-09-01
影响因子：
2.7
通讯作者：
Cuny, Gregory D.
中科院分区：
文献类型：
--
作者：
Choi, Sungwoon;Keys, Heather;Staples, Richard J.;Yuan, Junying;Degterev, Alexei;Cuny, Gregory D.
坏死下垂是一种受调节的不依赖caspase的细胞死亡途径，其形态特征类似于被动的不受调节的坏死。到目前为止，已经报道了几种不同结构类型的坏死性下垂抑制剂，包括一系列3,3a,4,5-四氢- 2h -苯并[g]茚唑（称为Nec-3系列），在细胞检测中显示出有效的活性。然而，三环坏死性下垂抑制剂在小鼠肝微粒体中的稳定性评估表明，它们被迅速降解。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和在三环2位的乙酰胺上引入亲水性取代基（即α-羟基），可以提高肝微粒体的稳定性，而不会显著影响抑制坏死的活性。利用5,5-二氧基-3-苯基-2,3,3a，4-四氢-[1]苯并噻唑类[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，坏死性下垂抑制活性没有维持。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性他汀类似物（例如33，LDN-193191）的策略，可能适用于体内研究。
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.
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DOI：
10.1152/ajpheart.00935.2003
发表时间：
2004-05-01
影响因子：
4.8
作者：
McCully, JD;Wakiyama, H;Levitsky, S
通讯作者：
Levitsky, S
影响因子：
14.8
作者：
Degterev, Alexei;Hitomi, Junichi;Yuan, Junying
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影响因子：
14.8
作者：
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影响因子：
2.7
作者：
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通讯作者：
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影响因子：
4.2
作者：
Rosenbaum DM;Degterev A;David J;Rosenbaum PS;Roth S;Grotta JC;Cuny GD;Yuan J;Savitz SI
通讯作者：
Savitz SI