4,5-Disubstituted-1,3-oxazolidin-2-imine derivatives: a new class of orally bioavailable nitric oxide synthase inhibitor
Introduction
There has been extensive scientific interest in the fundamental biochemistry and diverse physiological roles of nitric oxide (NO) since this simple gaseous radical molecule was first shown to have actions identical to those proposed for the endothelium-derived relaxing factor.1, 2 NO is produced by oxidation of l-arginine catalyzed by nitric oxide synthase (NOS) which utilizes molecular oxygen and cofactors.3, 4 NOS has been divided into two major sub-enzymes, that is, a constitutive NOS (cNOS), which is found in the vascular endothelium and in the brain, and an inducible NOS (iNOS), which is present in activated macrophages. Although the major function of iNOS is thought to serve in host defense mechanism, several studies have indicated that iNOS is also implicated in NO excessive production which causes inflammatory diseases such as hypotension,5 rheumatoid arthritis6 and colitis.7 On the other hand, cNOS has been further subdivided into endothelial NOS (eNOS), which is implicated in blood pressure regulation,8 and neuronal NOS (nNOS), which regulates neuronal transmission.9 Indeed, structural analogues of l-arginine such as NG-nitro-l-arginine (l-NNA), NG-monomethyl-l-arginine (l-NMMA) and NG-nitro-l-arginine methyl ester (l-NAME) have been synthesized and investigated in connection with a number of inflammation diseases in animal models as well as clinical trials. However, due to lack of selectivity for iNOS, no compound has been approved for the treatment of these conditions. Therefore potent and selective iNOS inhibitors that do not interfere with cNOS physiological functions have long been needed.
To date, non-l-arginine type iNOS selective inhibitors such as S-ethylisothiourea,10 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine,10 2-iminopiperidines,11 2-aminopyridine12 and 1,2-dihydro-4-quinazolinamine13 have been reported. Among these inhibitors, (1S,5S,6R,7R)-7-chloro-3-imino-5-methyl-2-azabicyclo[4.1.0]heptane hydrochloride (ONO-1714)14 and S-[2-[(1-iminoethyl)amino]ethyl]-l-homocysteine (GW274150)15 have been reported to potently and selectively inhibit iNOS and are currently undergoing evaluation in clinical Phase II and I trials, respectively. To synthesize compounds which show more selectivity for iNOS than ONO-1714 dose has been obvious interest to us, because, to our knowledge, ONO-1714 is the most proceeding compound as iNOS inhibitor in clinical trial and because the more selectivity would lead to the less side effect.
In our search for a novel class of iNOS inhibitors by means of random screening, we have found that the 1,3-oxazolidin-2-imine Figure 1, Chart 1 (Fig. 1) weakly inhibits iNOS with an IC50 value of 7.9 μM. Further modification of this compound resulted in the discovery of a new series of 1,3-oxazolidin-2-imine derivatives with improved inhibitory activity and selectivity for iNOS. Here, we report the synthesis of these new compounds and their structure–activity relationships (SARs).
Section snippets
Results and discussion
Starting from the 1,3-oxazolidin-2-imine (Figure 1, Chart 1), we first found that the 5-bromomethyl-1,3-oxazolidin-2-imine (2) potently inhibits iNOS with an IC50 value 16-fold that of Figure 1, Chart 1 (IC50=0.50 μM versus 7.9 μM, Table 1). This finding led us to suggest that introduction of an appropriately-sized hydrophobic alkyl group at the 4- or 5-position of Figure 1, Chart 1 would increase the inhibitory activity and selectivity for iNOS (Chart 1).
First, the monosubstituted
Conclusion
The series of 1,3-oxazolidin-2-imine derivatives described here represents a new class of iNOS inhibitor. The SARs of these novel inhibitors revealed that introduction of small substituents into the 1,3-oxazolidine ring enhances both the inhibitory activity and selectivity for iNOS. In addition, oral administration of selected 1,3-oxazolidin-2-imine derivatives attenuates the rise of plasma nitrite/nitrate levels induced by LPS in mice. These findings would aid in the design of more potent and
Acknowledgements
We gratefully acknowledged Dr. Nobuhide Watanabe and Dr. Katsumi Chiba for the thorough and helpful comments on this letter.
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