title: New antithrombotics with an indazole structure.
abstract: Fifteen new indazole derivatives have been synthesized. In the Born test, compounds (4f) and (4g) were most active. They inhibited the blood platelet aggregation induced by collagen with an IC(50) = 85 or 90 microM, respectively. After oral administration to rats (60 mg/kg) three of the compounds significantly inhibited the formation of thrombi in arterioles and venules. The strongest effect was observed with (4j) which showed an inhibition of 15% in arterioles and 7% in venules. Further experiments showed that compound (4j) does not mediate these effects by activating soluble guanylate cyclase, but likely by inhibiting phosphodiesterase isoform PDE 5.
authors.affiliation: Institut für Pharmazie, Freie Universität Berlin, Berlin, Germany.
authors.forename: Ali Kemal
authors.initials: AK
authors.lastname: Yildiz
authors.forename: Klaus
authors.initials: K
authors.lastname: Rehse
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.forename: Erwin
authors.initials: E
authors.lastname: Bischoff
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004789:Enzyme Activation / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013927:Thrombosis / Q000517:prevention & control
chemical_list: D005343:Fibrinolytic Agents; D007191:Indazoles; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; C517384:Pde5a protein, rat; D006162:Guanylate Cyclase