title: Active site-directed plasmin inhibitors: Extension on the P2 residue.
abstract: Based on the structure of YO-2 [N-(trans-4-aminomethylcyclohexanecarbonyl)-l-Tyr(O-picolyl)-NH-octyl], active site-directed plasmin (Plm) inhibitors were explored. The picolyl moiety in the Tyr(O-picolyl) residue (namely, the P2 residue) was replaced with smaller or larger groups, such as hydrogen, tert-butyl, benzyl, (2-naphthyl)methyl, and (quinolin-2-yl)methyl. Those efforts produced compound 17 {N-(trans-4-aminomethylcyclohexanecarbonyl)-l-Tyr[O-(quinolin-2-yl)methyl]-NH-octyl} [IC50=0.22 and 77μM for Plm and urokinase (UK), respectively], which showed not only 2.4-fold greater Plm inhibition than YO-2, but also an improvement in selectivity (Plm/UK) by 35-fold. The docking experiments of the Plm-17 complexes disclosed that the amino group of the tranexamyl moiety interacted with the side-chain of Asp753 which formed S1 site.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan; Cooperative Research Center for Life Science, Kobe Gakuin University, Kobe 650-8586, Japan.
authors.forename: Koushi
authors.initials: K
authors.lastname: Hidaka
authors.affiliation: Computer-Aided Molecular Modeling Research Center, Kansai, Nishinomiya 663-8241, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Gohda
authors.affiliation: Faculty of Clinical Nutrition, Hiroshima International University, Kure 737-0112, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Teno
authors.affiliation: Research Projects on Thrombosis and Haemostatsis, Kobe 655-0033, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Wanaka
authors.affiliation: Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan; Cooperative Research Center for Life Science, Kobe Gakuin University, Kobe 650-8586, Japan. Electronic address: tsuda@pharm.kobegakuin.ac.jp.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuda
mesh_terms: D000933:Antifibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005341:Fibrinolysin / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000037:antagonists & inhibitors / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000933:Antifibrinolytic Agents; D014443:Tyrosine; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator
keywords: Active site-directed inhibitor; Plasmin inhibitor; Selectivity; Urokinase