Evaluation of 3-substituted arginine analogs as selective inhibitors of human nitric oxide synthase isozymes.

Article Details

Citation

Ijuin R, Umezawa N, Nagai S, Higuchi T

Evaluation of 3-substituted arginine analogs as selective inhibitors of human nitric oxide synthase isozymes.

Bioorg Med Chem Lett. 2005 Jun 2;15(11):2881-5. Epub 2005 Apr 25.

PubMed ID
15911272 [ View in PubMed
]
Abstract

Nitric oxide (NO), a mediator of various physiological and pathophysiological processes, is synthesized by three isozymes of nitric oxide synthase (NOS). In developing candidate clinical drugs, it is very important not to inhibit endothelial NOS, because it plays an important role in maintaining normal blood pressure and flow. Here, we describe the design, synthesis and human NOS-inhibitory activities of S-methyl-L-isothiocitrulline-based 3-substituted arginine analogs. The 3R*-methyl compound 4, which has an S-methyl isothiourea moiety, inhibited nNOS and iNOS, but not eNOS (IC(50) > 1 mM). However, the 3R*-methyl compound 7, bearing a 5-iminoethyl moiety, did not inhibit any of the NOS isozymes, although L-N-iminoethylornithine (L-NIO) potently inhibited all three. A computational docking study was carried out to investigate the mechanism of the isozyme selectivity.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
N(G)-IminoethylornithineNitric oxide synthase, endothelialIC 50 (nM)6000N/AN/ADetails