4,5-Dialkylsubstituted 2-imino-1,3-thiazolidine derivatives as potent inducible nitric oxide synthase inhibitors

A series of 2-imino-1,3-thiazolidine derivatives have been synthesized and their inhibitory activity against iNOS and selectivity for iNOS both in vitro and in vivo was described. In the course of our search for selective iNOS inhibitors, we have previously reported that 2-imino-1,3-oxazolidine derivatives ( 1) and 2-aminothiazole derivatives ( 2) are selective iNOS inhibitors. In order to find more potent iNOS inhibitors, we focused our efforts on the synthesis and evaluation of the inhibitory activity against iNOS and selectivity for iNOS both in vitro and in vivo of a series of 2-imino-1,3-thiazolidine derivatives ( 3), which are analogues of 1 and 2. Our results show that among the compounds synthesized (4 R,5 R)-5-ethyl-2-imino-4-methyl-1,3-thiazolidine [(4 R,5 R)- 14a: ES-1537] exhibited potent inhibitory activity and selectivity for iNOS. In addition, ES-1537 had good pharmacokinetic profile in rats with BA value of 80%. It is therefore expected that ES-1537 may be therapeutically useful for the treatment of diseases related to excess production of NO.