910098-46-3Relevant academic research and scientific papers
Pyrolo[1,2:4,5]-1,4-dioxopyrazino[1,2:1,6]pyrido[3,4-b]indoles: A Group of Urokinase Inhibitors, their Synthesis, and Stereochemistry-Dependent Activity
Liu, Jiawang,Wang, Yuji,Yang, Yifan,Jiang, Xueyun,Zhao, Ming,Wang, Wenjing,Wu, Guofeng,Wu, Jianhui,Zheng, Meiqing,Peng, Shiqi
, p. 2312 - 2322 (2011)
Antifibrinolytic agents are required during complex surgeries to decrease bleeding; their pro-thrombotic potency and efficacy in causing hemostasis has attracted much attention. To discover new inhibitors of urokinase with high selectivity for antifibrinolytic effects over pro-thrombotic effects, the 12-position of (5aS,12S,14aS)- and (5aS,12R,14aS)-5,14-dioxo-1,2,3,5,5a,6,11, 12,14,14a-decahydro-5H,14H-pyrolo[1,2:4,5]pyrazino[1,2:1,6]pyrido[3,4-b]indoles were modified with L-Ala, L-Asp, L-Phe, L-Trp, L-Lys, L-Ser, Gly, and L-Leu to provide 16 (5aS,12S,14aS) and (5aS,12R,14aS) derivatives. In a murine bleeding model, the (5aS,12S,14aS) derivatives containing L-Ala, L-Asp, L-Phe, and L-Trp induced blood coagulation for the treated mice; they also stimulated thrombus formation in a rat thrombosis model, but the other derivatives inhibited thrombosis. The most potent compound, the L-Asp derivative, showed a good therapeutic window: the minimum effective dose for coagulation was -1, whereas at 10nmolkg-1, no pro-thrombotic effect was observed. This type of coagulation action was correlated with a mechanism of urokinase inhibition, and these results could lead to the discovery of novel urokinase inhibitors. Stop the clot: Small molecular antifibrinolytic agents in clinical use such as tranexamic acid carry the risk of prompting thrombus formation. Herein we present an investigation of pyrolo[1,2:4,5]-1,4-dioxopyrazino[1,2:1,6]pyrido[3,4-b]indoles (DAPPP), some of which show strong hemostatic activities invivo. The most potent compound, 5c, has a good therapeutic window for antifibrinolytic therapy.
