title: Novel thrombin inhibitors incorporating non-basic partially saturated heterobicyclic P1-arginine mimetics.
abstract: The design, synthesis and biological activity of non-covalent thrombin inhibitors incorporating 4,5,6,7-tetrahydroindazole, 2-methyl-4,5,6,7-tetrahydroindazole, 4,5,6,7-tetrahydroisoindole, 5,6,7,8-tetrahydroquinazoline and 5,6,7,8-tetrahydroquinazolin-2-amine as novel, partially saturated, heterobicyclic P(1)-arginine side-chain mimetics is described. The binding mode of the most potent candidate in the series co-crystallized with human alpha-thrombin, which exhibited an in vitro K(i) of 140nM and more that 478-fold selectivity against trypsin, is discussed.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia.
authors.forename: Lucija
authors.initials: L
authors.lastname: Peterlin-Masic
authors.forename: Gregor
authors.initials: G
authors.lastname: Mlinsek
authors.forename: Tomaz
authors.initials: T
authors.lastname: Solmajer
authors.forename: Alenka
authors.initials: A
authors.lastname: Trampus-Bakija
authors.forename: Mojca
authors.initials: M
authors.lastname: Stegnar
authors.forename: Danijel
authors.initials: D
authors.lastname: Kikelj
mesh_terms: D001120:Arginine / Q000737:chemistry*; D001665:Binding Sites; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology; D002937:Cinoxacin / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007191:Indazoles / Q000737:chemistry; D007211:Indoles / Q000737:chemistry; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D007191:Indazoles; D007211:Indoles; D001120:Arginine; D014357:Trypsin; D013917:Thrombin; D002937:Cinoxacin