title: 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.
abstract: 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 nmol kg(-1), whereas at 10 nmol kg(-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.
authors.affiliation: College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China.
authors.forename: Jiawang
authors.initials: J
authors.lastname: Liu
authors.forename: Yuji
authors.initials: Y
authors.lastname: Wang
authors.forename: Yifan
authors.initials: Y
authors.lastname: Yang
authors.forename: Xueyun
authors.initials: X
authors.lastname: Jiang
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Wenjing
authors.initials: W
authors.lastname: Wang
authors.forename: Guofeng
authors.initials: G
authors.lastname: Wu
authors.forename: Jianhui
authors.initials: J
authors.lastname: Wu
authors.forename: Meiqing
authors.initials: M
authors.lastname: Zheng
authors.forename: Shiqi
authors.initials: S
authors.lastname: Peng
mesh_terms: D000818:Animals; D000933:Antifibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D001798:Blood Proteins / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013927:Thrombosis / Q000188:drug therapy; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C571078:5,14-dioxo-12-(2-phenylalanine-N-ylethyl-1-yl)-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)indole; D000933:Antifibrinolytic Agents; D001798:Blood Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D007211:Indoles; C031220:urokinase inhibitor; D010649:Phenylalanine; D014568:Urokinase-Type Plasminogen Activator