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Synthesis and biological characterization of L-N(6)-(1-iminoethyl)lysine 5-tetrazole-amide, a prodrug of a selective iNOS inhibitor.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2002 Apr 11; Vol. 45 (8), pp. 1686-9. - Publication Year :
- 2002
-
Abstract
- The 5-tetrazole amide of L-N(6)-(1-iminoethyl)lysine (L-NIL), L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide (1), has been prepared and evaluated. In contrast to L-NIL, 1 is a stable, nonhygroscopic, crystalline solid. Unlike L-NIL, 1 has minimal inhibitory activity in vitro on human inducible nitric oxide synthase (iNOS). However, it is rapidly converted in vivo to L-NIL and produces dose-dependent inhibition of iNOS in acute and chronic models of inflammation in the rodent with efficacy comparable to L-NIL. In addition, both 1 and L-NIL exhibit significant and comparable in vivo selectivity for the inhibition of iNOS vs endothelial NOS. Doses approximately 80-fold greater than those that inhibited inflammation do not elevate systemic blood pressure. In summary, both the physical properties and the pharmacological profile of 1 make it an ideal molecule for preclinical and clinical studies on the role of selective iNOS inhibitors in mediating inflammatory disease processes.
- Subjects :
- Acute Disease
Administration, Oral
Animals
Arthritis, Experimental pathology
Carrageenan
Chronic Disease
Crystallization
Edema chemically induced
Edema enzymology
Edema pathology
Enzyme Inhibitors chemistry
Enzyme Inhibitors metabolism
Homoarginine analogs & derivatives
Homoarginine chemistry
Homoarginine metabolism
Humans
Isoenzymes antagonists & inhibitors
Nitric Oxide Synthase Type I
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
Prodrugs chemistry
Prodrugs metabolism
Rats
Recombinant Proteins antagonists & inhibitors
Enzyme Inhibitors chemical synthesis
Homoarginine chemical synthesis
Lysine analogs & derivatives
Lysine chemistry
Nitric Oxide Synthase antagonists & inhibitors
Prodrugs chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 45
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 11931623
- Full Text :
- https://doi.org/10.1021/jm010420e