Structure-activity relationship of novel and known inhibitors of human dimethylarginine dimethylaminohydrolase-1: alkenyl-amidines as new leads.
Recent studies demonstrated that inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity could be a new strategy to indirectly affect nitric oxide (NO) formation by elevating N(omega)-methylated L-arginine (NMMA, ADMA) levels. This approach is an alternate strategy for the treatment of diseases associated with increased NO-concentrations. To date, three classes of potent inhibitors are known: (1) pentafluorophenyl sulfonates (IC(50)=16-58 microM, PaDDAH), which are also inhibitors for the arginine deiminase; (2) the most potent inhibitors are based on indolylthiobarbituric acid (IC(50)=2-17 microM, PaDDAH), which were identified by virtual modelling; and (3) L-arginine analogs, whose best representative is N(omega)-(2-methoxyethyl)-L-arginine (IC(50)=22 microM, rat DDAH). Based on these known structures, we aimed to develop inhibitors for the human DDAH-1 with improved potency and better relative selectivity for DDAH-1 over NOS. Particularly, the binding pocket of the guanidine-moiety was investigated by screening differently substituted guanidines, amidines and isothioureas in order to collect information on possible binding modes in the active site. All substances were tested in a plate-reader format and HPLC assay and several potent inhibitors were identified with K(i)-values varying from 2 to 36 microM, with N(5)-(1-iminobut-3-enyl)-L-ornithine (L-VNIO) being the most potent inhibitor of the human DDAH-1 so far described. Besides these potent inhibitors alternate substrates for hDDAH-1 were identified as well.
Kotthaus
Jürke
J
Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute, Christian-Albrechts-University of Kiel, Gutenbergstrasse 76-78, D-24118 Kiel, Germany.
Schade
Dennis
D
Muschick
Nikola
N
Beitz
Eric
E
Clement
Bernd
B
D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009569:Nitric Oxide / Q000502:physiology; D020030:Nitric Oxide Donors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
D000578:Amidines; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; D000581:Amidohydrolases; C059999:dimethylargininase