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 I,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. (C) 1998 Elsevier Science Ltd. All rights reserved.