title: 2-Substituted (S)-2-(3,3-dimethyl-1-oxo-10,10a-dihydroimidazo[1,5-b]isoquinolin-2(1H,3H,5H)-yl)acetic acids: Conformational prediction, synthesis, anti-thrombotic and vasodilative evaluation.
abstract: (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (TIC) can inhibit thrombosis by inhibiting platelet aggregation. The investigation of amino acids modified TIC reveals that a stretching conformation is critical for high anti-thrombotic activity. The conformational modeling shows that introducing a ring into amino acid modified TIC results in a desirable stretching conformation. According to this hypothesis, we synthesized seventeen novel 2-substituted (S)-2-(3,3-dimethyl-1-oxo-10,10a-dihydroimidazo[1,5-b]isoquinolin-2(1H,3H,5H)-yl)acetic acids (5a-q). In the in vitro anti-platelet aggregation assay, for ADP-induced platelet aggregation the IC(50) values of 5a-q are 1.8-3.4-folds lower than that of TIC. In the in vivo anti-thrombotic assay, the effective dose of 5a-q was 167-folds lower than that of TIC. The vessel strip assay showed that 5a-q had mild vasorelaxation activity.
authors.affiliation: Capital Medical University, Beijing, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Le
authors.initials: L
authors.lastname: Peng
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Jiawang
authors.initials: J
authors.lastname: Liu
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Zhang
authors.forename: Yuji
authors.initials: Y
authors.lastname: Wang
authors.forename: Jianhui
authors.initials: J
authors.lastname: Wu
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Shiqi
authors.initials: S
authors.lastname: Peng
mesh_terms: D000818:Animals; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D044005:Tetrahydroisoquinolines; C078986:1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid