TY - JOUR
T1 - Imidazole-containing amino acids as selective inhibitors of nitric oxide synthases
AU - Lee, Younghee
AU - Martasek, Pavel
AU - Roman, Linda J.
AU - Masters, Bettie Sue Siler
AU - Silverman, Richard B.
N1 - Funding Information:
We are grateful to the National Institutes of Health for financial support of this research to R.B.S. (GM49725) and B.S.S.M. (GM52419) and to the Robert A. Welch Foundation (AQ-1192) for financial support to B.S.S.M. Sincere thanks go to Professor Michael A. Marletta (University of Michigan) for providing the E. coli cells with an overexpression system for murine macrophage iNOS.
PY - 1999/9
Y1 - 1999/9
N2 - Two series of imidazole-containing amino acids (1a-e and 2a-c), all larger homologues and analogues of L-histidine, were prepared. Since imidazole and phenyl substituted imidazoles have been reported to be inhibitors of NOS and the mode of action of these compounds as heme ligands is a potential mechanism of inhibitory action, we designed imidazole-containing amino acids as combined inhibitors at both the amino acid as well as heme binding sites. To study the influence of the distance between the amino acid moiety and the imidazole moiety on inhibitory potency, the number of carbons between these two functional groups was varied from two to six. The structure-activity relationships of this class of inhibitors can be correlated with the distance between the heme and the amino acid binding sites of the enzyme. Two of the compounds (1b and 1d) with three and five methylenes between the imidazole and amino acid functional groups, respectively, were found to be potent and selective inhibitors for nNOS and iNOS over eNOS. When phenyl was substituted on the nitrogen of the imidazole, both the potency and isoform selectivity diminished.
AB - Two series of imidazole-containing amino acids (1a-e and 2a-c), all larger homologues and analogues of L-histidine, were prepared. Since imidazole and phenyl substituted imidazoles have been reported to be inhibitors of NOS and the mode of action of these compounds as heme ligands is a potential mechanism of inhibitory action, we designed imidazole-containing amino acids as combined inhibitors at both the amino acid as well as heme binding sites. To study the influence of the distance between the amino acid moiety and the imidazole moiety on inhibitory potency, the number of carbons between these two functional groups was varied from two to six. The structure-activity relationships of this class of inhibitors can be correlated with the distance between the heme and the amino acid binding sites of the enzyme. Two of the compounds (1b and 1d) with three and five methylenes between the imidazole and amino acid functional groups, respectively, were found to be potent and selective inhibitors for nNOS and iNOS over eNOS. When phenyl was substituted on the nitrogen of the imidazole, both the potency and isoform selectivity diminished.
KW - Histidine analogues
KW - Imidazole-containing amino acids
KW - Inhibitors
KW - Nitric oxide synthase
UR - http://www.scopus.com/inward/record.url?scp=0032860443&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032860443&partnerID=8YFLogxK
U2 - 10.1016/S0968-0896(99)00117-0
DO - 10.1016/S0968-0896(99)00117-0
M3 - Article
C2 - 10530943
AN - SCOPUS:0032860443
VL - 7
SP - 1941
EP - 1951
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 9
ER -