S. Ulhaq et al., S-2-amino-5-azolylpentanoic acids related to L-ornithine as inhibitors of the isoforms of nitric oxide synthase (NOS), BIO MED CH, 6(11), 1998, pp. 2139-2149
S-2-Amino-5-(2-aminoimidazol-1-yl)pentanoic acid and S-2-amino-5-(2-nitroim
idazol-1-yl)pentanoic acid have been used as weakly inhibitory lead compoun
ds in the design of 2-amino-5-azolylpentanoic acids which are more potent i
n their inhibition of nitric oxide synthases. Treatment of 2-(Boc-amino)-5-
bromopentanoic acid t-butyl ester with appropriate imidazoles and 1,2,4-tri
azoles and with tetrazole under basic conditions, followed by acidolytic de
protection, gave many of the required 2-amino-5-azolylpentanoic acids. Tetr
azole was alkylated at 1-N and at 2-N in approximately equal amounts wherea
s 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 precu
rsor with 1-cyano-4-dimethylaminopyridine. Of this series of compounds, 2-a
mino-5-(imidazol-1-yl)pentanoic acid was identified as the most potent memb
er against rat iNOS, rat nNOS and a human-derived cNOS. Examination of the
structure-activity relationships for the identity and substitution of the a
zoles 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 Lt
d. All rights reserved.