Time-dependence and preliminary SAR studies in inhibition of nitric oxide synthase isoforms by homologues of thiocitrulline.
Treatment of N(alpha)-Cbz-N(epsilon)-(2-hydroxyethylaminothiocarbonyl)-L-lysine N-(2-hydroxyethyl)amide with boiling hydrochloric acid gave N(epsilon)-(4,5-dihydrothiazol-2-yl)-L-lysine. This was a weak and non-isoform selective inhibitor of NOS, whereas N(epsilon)-aminothiocarbonyl-L-lysine and its methyl ester were potent, with IC(50)=13 and 18 microM, respectively, against human iNOS and IC(50)=3 and 8 microM, respectively, against rat nNOS. Time dependence was observed for inhibition of nNOS by the ester.
Goodyer
Claire L M
CL
Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
Chinje
Edwin C
EC
Jaffar
Mohammed
M
Stratford
Ian J
IJ
Threadgill
Michael D
MD
D000818:Animals; D002956:Citrulline / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D007527:Isoenzymes; D011994:Recombinant Proteins; C086715:thiocitrulline; D019323:omega-N-Methylarginine; D002956:Citrulline; C496320:NOS1 protein, human; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496322:Nos1 protein, rat; C496318:Nos2 protein, rat; D013890:Thiourea