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To discover new inhibitors of urokinase with high selectivity for antifibrinolytic effects over pro\u2010thrombotic effects, the 12\u2010position of (5a<jats:italic>S<\/jats:italic>,12<jats:italic>S<\/jats:italic>,14a<jats:italic>S<\/jats:italic>)\u2010 and (5a<jats:italic>S<\/jats:italic>,12<jats:italic>R<\/jats:italic>,14a<jats:italic>S<\/jats:italic>)\u20105,14\u2010dioxo\u20101,2,3,5,5a,6,11, 12,14,14a\u2010decahydro\u20105<jats:italic>H<\/jats:italic>,14<jats:italic>H<\/jats:italic>\u2010pyrolo[1,2:4,5]pyrazino[1,2:1,6]pyrido[3,4\u2010<jats:italic>b<\/jats:italic>]indoles were modified with <jats:sc>L<\/jats:sc>\u2010Ala, <jats:sc>L<\/jats:sc>\u2010Asp, <jats:sc>L<\/jats:sc>\u2010Phe, <jats:sc>L<\/jats:sc>\u2010Trp, <jats:sc>L<\/jats:sc>\u2010Lys, <jats:sc>L<\/jats:sc>\u2010Ser, Gly, and <jats:sc>L<\/jats:sc>\u2010Leu to provide 16 (5a<jats:italic>S<\/jats:italic>,12<jats:italic>S<\/jats:italic>,14a<jats:italic>S<\/jats:italic>) and (5a<jats:italic>S<\/jats:italic>,12<jats:italic>R<\/jats:italic>,14a<jats:italic>S<\/jats:italic>) derivatives. In a murine bleeding model, the (5a<jats:italic>S<\/jats:italic>,12<jats:italic>S<\/jats:italic>,14a<jats:italic>S<\/jats:italic>) derivatives containing <jats:sc>L<\/jats:sc>\u2010Ala, <jats:sc>L<\/jats:sc>\u2010Asp, <jats:sc>L<\/jats:sc>\u2010Phe, and <jats:sc>L<\/jats:sc>\u2010Trp 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 <jats:sc>L<\/jats:sc>\u2010Asp derivative, showed a good therapeutic window: the minimum effective dose for coagulation was &lt;1\u2005nmol\u2009kg<jats:sup>\u22121<\/jats:sup>, whereas at 10\u2005nmol\u2009kg<jats:sup>\u22121<\/jats:sup>, no pro\u2010thrombotic 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.<\/jats:p>","DOI":"10.1002\/cmdc.201100345","type":"journal-article","created":{"date-parts":[[2011,9,27]],"date-time":"2011-09-27T18:41:00Z","timestamp":1317148860000},"page":"2312-2322","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Pyrolo[1,2:4,5]\u20101,4\u2010dioxopyrazino[1,2:1,6]pyrido[3,4\u2010<i>b<\/i>]indoles: A Group of Urokinase Inhibitors, their Synthesis, and Stereochemistry\u2010Dependent Activity"],"prefix":"10.1002","volume":"6","author":[{"given":"Jiawang","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuji","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yifan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xueyun","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenjing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guofeng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhui","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meiqing","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiqi","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2011,9,23]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1213\/ane.0b013e318182252b"},{"key":"e_1_2_6_2_2","unstructured":"D.\u2005A. 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