title: Synthesis and evaluation of tripeptidic plasmin inhibitors with nitrile as warhead.
abstract: Plasmin is best known as the key molecule in the fibrinolytic system, which is critical for clot lysis and can initiate matrix metalloproteinase (MMP) activation cascade. Along with MMP, plasmin is suggested to be involved in physiological processes that are linked to the risk of carcinoma formation. Plasmin inhibitors could be perceived as a promising new principle in the treatment of diseases triggered by plasmin. On the basis of the peptidic sequence derived from the synthetic plasmin substrate, a series of peptidic plasmin inhibitors possessing nitrile as warhead were prepared and evaluated for their inhibitory activities against plasmin and other serine proteases, plasma kallikrein and urokinase. The most potent peptidic inhibitors with the nitrile warhead exhibit the potency toward plasmin (IC(50)  = 7.7-11 μM) and are characterized by their selectivity profile against plasma kallikrein and urokinase. The results and molecular modeling of the peptidic inhibitor complexed with plasmin reveal that the P2 residue makes favorable contacts with the open binding pocket comprising the S2 and S3 subsites of plasmin.
authors.affiliation: Hiroshima International University, Faculty of Pharmaceutical Sciences, 5-1-1, Hirokoshingai, Kure, Hiroshima, 737-0112, Japan. n-teno@ps.hirokoku-u.ac.jp
authors.forename: Naoki
authors.initials: N
authors.lastname: Teno
authors.forename: Tadamune
authors.initials: T
authors.lastname: Otsubo
authors.forename: Keigo
authors.initials: K
authors.lastname: Gohda
authors.forename: Keiko
authors.initials: K
authors.lastname: Wanaka
authors.forename: Takuya
authors.initials: T
authors.lastname: Sueda
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ikeda
authors.forename: Akiko
authors.initials: A
authors.lastname: Hijikata-Okunomiya
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuda
mesh_terms: D004305:Dose-Response Relationship, Drug; D005341:Fibrinolysin / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020842:Plasma Kallikrein / Q000037:antagonists & inhibitors; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors
chemical_list: D009570:Nitriles; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; D020842:Plasma Kallikrein; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator