title: Synthesis and evaluation of trans 3,4-cyclopropyl L-arginine analogues as isoform selective inhibitors of nitric oxide synthase.
abstract: Four optically pure conformationally restricted L-arginine analogues syn- 1 and anti- 2 trans-3,4-cyclopropyl L-arginine, and syn- 3 and anti-trans-3,4-cyclopropyl N-(1-iminoethyl) L-ornithine 4 were synthesized. These compounds were tested as potential inhibitors against the three isoforms of nitric oxide synthase (NOS). Compound 1 was determined to be a poor substrate of NOS, while compound 2 was determined to be a poor mixed type inhibitor and did not exhibit any isoform selectivity. Syn- 3 and anti-trans-3,4-cyclopropyl N-(1-iminoethyl) L-ornithine 4 were found to be competitive inhibitors of NOS. These compounds were time dependent inhibitors of inducible NOS (iNOS), but not of neuronal NOS (nNOS) or endothelial NOS (eNOS). Compound 3 was 10- to 100-fold more potent an inhibitor than 4, exhibited a 5-fold increase in nNOS/iNOS and eNOS/iNOS selectivity over 4, and displayed tight binding characteristics against iNOS. These results indicate that the relative configuration of the cyclopropyl ring in the L-arginine analogues significantly affects their inhibitory potential and NOS isoform selectivity.
authors.affiliation: Department of Chemistry, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Dan
authors.initials: D
authors.lastname: Fishlock
authors.forename: Basil
authors.initials: B
authors.lastname: Perdicakis
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Montgomery
authors.forename: J Guy
authors.initials: JG
authors.lastname: Guillemette
authors.forename: Eric
authors.initials: E
authors.lastname: Jervis
authors.forename: Gilles A
authors.initials: GA
authors.lastname: Lajoie
mesh_terms: D001120:Arginine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007536:Isomerism; D007700:Kinetics; D008968:Molecular Conformation; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III
chemical_list: D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D007527:Isoenzymes; C478780:trans 3,4-cyclopropyl L-arginine; D001120:Arginine; C496320:NOS1 protein, human; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III