title: 4,5-dialkylsubstituted 2-imino-1,3-thiazolidine derivatives as potent inducible nitric oxide synthase inhibitors.
abstract: 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 (4R,5R)-5-ethyl-2-imino-4-methyl-1,3-thiazolidine [(4R,5R)-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.
authors.affiliation: Chemistry Research Laboratories, Dainippon Pharmaceutical Co. Ltd, Enoki-cho 33-94, Suita, Osaka 564-0053, Japan. shigeo.ueda@dainippon-pharm.co.jp
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ueda
authors.forename: Hideo
authors.initials: H
authors.lastname: Terauchi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yano
authors.forename: Masashi
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Taeko
authors.initials: T
authors.lastname: Kubo
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kyoya
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Motoharu
authors.initials: M
authors.lastname: Ido
authors.forename: Motoji
authors.initials: M
authors.lastname: Kawasaki
mesh_terms: D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000097:blood / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D013844:Thiazoles; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat