Arylazoamidoximes and related compounds as NO-modulators.
Three amidinoarylhydrazines 1, three arylazoamidines 2, and nine arylazoamidoximes 3 have been synthesized and investigated for their potential to function as nitric oxide (NO) modulators. In-vitro studies demonstrated that 2 and 3 inhibited platelet aggregation (2c, IC(50 )= 3 microM) which could also be shown in vivo by inhibition of thrombus formation in arterioles (3a, 22%). Moreover, for all compounds antihypertensive effects were examined in vivo with SHR rats, with 2a being the most potent candidate by lowering blood pressure by 19%. However, no common underlying mechanism of action could be shown. Some of these compounds released HNO non-enzymatically. Incubations with NO synthase isoforms (NOSs) revealed, that compounds 1 to 3 were weak substrates for NOSs but arylazoamidoximes 3 remarkably elevated the NOSs activity in the presence of L-arginine (3h, up to fivefold). In addition, we examined effects on arginase and dimethylarginine dimethylaminohydrolase (DDAH), two further enzymes involved in the complex regulation of NO biosynthesis, to elucidate whether the observed in-vivo effects can be traced back to their modulation. Furthermore, the metabolic fate of arylazoamidoximes 3 was addressed by investigation of a possible N-reductive biotransformation. In summary, novel NO-modulating compound classes are presented, among which arylazoamidoximes 3 are potent activators of NOS isoforms, and arylazoamidines 2 exert in-vivo effects by unknown mechanisms.
Schröder
Alexander
A
Pharmaceutical Institute, Freie Universität Berlin, Königin-Luise-Strasse 2 + 4, Berlin, Germany.
Kotthaus
Jürke
J
Schade
Dennis
D
Clement
Bernd
B
Rehse
Klaus
K
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis*; D010091:Oximes / Q000138:chemical synthesis / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000494:pharmacology*
D005343:Fibrinolytic Agents; D010091:Oximes; D010975:Platelet Aggregation Inhibitors; D014665:Vasodilator Agents; D009569:Nitric Oxide