In:
ChemMedChem, Wiley, Vol. 6, No. 12 ( 2011-12-09), p. 2312-2322
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 (5a S ,12 S ,14a S )‐ and (5a S ,12 R ,14a S )‐5,14‐dioxo‐1,2,3,5,5a,6,11, 12,14,14a‐decahydro‐5 H ,14 H ‐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 (5a S ,12 S ,14a S ) and (5a S ,12 R ,14a S ) derivatives. In a murine bleeding model, the (5a S ,12 S ,14a S ) 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.
Type of Medium:
Online Resource
ISSN:
1860-7179
,
1860-7187
DOI:
10.1002/cmdc.201100345
Language:
English
Publisher:
Wiley
Publication Date:
2011
detail.hit.zdb_id:
2209649-8
SSG:
15,3
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