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A potent inhibitor of inducible nitric oxide synthase, ONO-1714, a cyclic amidine derivative.

Abstract：

:(1S,5S,6R,7R)-7-Chloro-3-imino-5-methyl-2-azabicyclo[4.1.0]heptane hydrochloride (ONO-1714), a novel cyclic amidine analogue, inhibits human inducible nitric oxide (iNOS) with a K(i) of 1.88 nM and rodent iNOS with similar potency in vitro. ONO-1714 was found to be 10-fold selective for human iNOS over human endothelial NOS (ecNOS). When the inhibitory activity of ONO-1714 was compared for iNOS, it was found to be 451-fold and >20,000-fold more potent than L-NMMA and aminoguanidine (AG), respectively. In terms of human iNOS selectivity, ONO-1714 was approximately 34- and 2-fold more selective for iNOS than L-NMMA and AG, respectively. ONO-1714 inhibited the LPS-induced elevation of plasma nitrate/nitrite in mice with an ID(50) value of 0.010 mg/kg, s.c. The maximum tolerated dose of ONO-1714 was 30 mg/kg, i.v. Thus, ONO-1714 represents one of the most potent iNOS inhibitors in vitro and in vivo to date and has great potentials for use as an inhibitor for clarifying the pathophysiological roles of iNOS and for use as a therapeutic agent.

journal_name

Biochem Biophys Res Commun

journal_title

Biochemical and biophysical research communications

authors

Naka M,Nanbu T,Kobayashi K,Kamanaka Y,Komeno M,Yanase R,Fukutomi T,Fujimura S,Seo HG,Fujiwara N,Ohuchida S,Suzuki K,Kondo K,Taniguchi N

doi

10.1006/bbrc.2000.2474

subject

Has Abstract

pub_date

2000-04-13 00:00:00

pages

663-7

issue

2

eissn

0006-291X

issn

1090-2104

pii

S0006-291X(00)92474-4

journal_volume

270

pub_type

杂志文章

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