title: Development of active center-directed plasmin and plasma kallikrein inhibitors and studies on the structure-inhibitory activity relationship.
abstract: The molecule of trans-4-aminomethylcyclohexanecarbonylphenylalanine 4-carboxymethylanilide (8), which is a potent and selective inhibitor of plasma kallikrein, can be divided into three parts (P1, P1' and P2'), each of which contains one of the rings. In order to study the role of each part in the manifestation of potent and selective inhibitory activity and the relationship between the structure and inhibitory activities toward plasmin, plasma kallikrein, urokinase and thrombin, each part was substituted with various other moieties to give many kinds of analogs and their inhibitory activities against the above enzymes were examined. Among them, trans-4-aminomethylcyclohexanecarbonyl-O-2-bromobenzyloxycarbon yltyrosine 4-acetylanilide (12) inhibited plasmin and plasma kallikrein with IC50 values of 2.3 x 10(-7) M and 3.7 x 10(-7) M, and K(i) values of 1.2 x 10(-7) M and 1.3 x 10(-7) M, respectively.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kobe-Gakuin University, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Teno
authors.forename: K
authors.initials: K
authors.lastname: Wanaka
authors.forename: Y
authors.initials: Y
authors.lastname: Okada
authors.forename: H
authors.initials: H
authors.lastname: Taguchi
authors.forename: U
authors.initials: U
authors.lastname: Okamoto
authors.forename: A
authors.initials: A
authors.lastname: Hijikata-Okunomiya
authors.forename: S
authors.initials: S
authors.lastname: Okamoto
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000032:analysis; D000818:Animals; D005341:Fibrinolysin / Q000037:antagonists & inhibitors*; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014148:Tranexamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000596:Amino Acids; C083108:4-aminomethylcyclohexanecarbonyl-O-2-bromobenzyloxycarbonyltyrosine 4-acetylanilide; C064866:PKSI 527; D014443:Tyrosine; D010649:Phenylalanine; D014148:Tranexamic Acid; D007610:Kallikreins; D005341:Fibrinolysin