S-2-amino-5-azolylpentanoic acids related to L-ornithine as inhibitors of the isoforms of nitric oxide synthase (NOS).
S-2-Amino-5-(2-aminoimidazol-1-yl)pentanoic acid and S-2-amino-5-(2-nitroimidazol-1-yl)pentanoic acid have been used as weakly inhibitory lead compounds in the design of 2-amino-5-azolylpentanoic acids which are more potent in their inhibition of nitric oxide synthases. Treatment of 2-(Boc-amino)-5-bromopentanoic acid t-butyl ester with appropriate imidazoles and 1,2,4-triazoles and with tetrazole under basic conditions, followed by acidolytic deprotection, gave many of the required 2-amino-5-azolylpentanoic acids. Tetrazole was alkylated at 1-N and at 2-N in approximately equal amounts whereas the 1,2,4-triazoles reacted principally at 1-N. A nitrile was introduced at the 2-position of the imidazole by reaction of the 2-unsubstituted precursor with 1-cyano-4-dimethylaminopyridine. Of this series of compounds, 2-amino-5-(imidazol-1-yl)pentanoic acid was identified as the most potent member against rat iNOS, rat nNOS and a human-derived cNOS. Examination of the structure-activity relationships for the identity and substitution of the azoles has led to the proposal of a model for the binding of the inhibitors to the binding site for the natural substrate.
Ulhaq
S
S
Department of Pharmacy & Pharmacology, University of Bath, UK.
Chinje
E C
EC
Naylor
M A
MA
Jaffar
M
M
Stratford
I J
IJ
Threadgill
M D
MD
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000201:enzymology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D008168:Lung / Q000201:enzymology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; 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; D009952:Ornithine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010421:Pentanoic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D010421:Pentanoic Acids; D009952:Ornithine; 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; C496321:Nos1 protein, mouse; C496322:Nos1 protein, rat; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat