title: Structure-activity relationships of 2-aminothiazole derivatives as inducible nitric oxide synthase inhibitor.
abstract: Nitric oxide synthase (NOS) has been divided into two major sub-enzymes, i.e. inducible NOS (iNOS) and constitutive NOS (cNOS). Although nitric oxide (NO) plays an important role as host defense mediator, excessive production of NO by iNOS has been involved in the pathology of many inflammatory diseases. Recently, we reported that the 2-imino-1,3-oxazolidine (1a) weakly inhibits iNOS and that introduction of an alkyl moiety on the oxazolidine ring of 1a enhances the inhibitory activity and selectivity for iNOS. In our search for better iNOS inhibitors, we focused our efforts on the 2-aminothiazole scaffold 3 as it possesses a ring similar to that of 1a. In this study, we evaluated the inhibitory activity of a series of 2-aminothiazole derivatives against both iNOS and neuronal NOS (nNOS). Our results show that introduction of appropriately-sized substituents at the 4- and 5-position of the 2-aminothiazole ring improves the inhibitory activity and selectivity for iNOS. We also found that the selectivity of 5a [5-(1-methyl)ethyl-4-methylthiazol-2-ylamine] and 5b [5-(1,1-dimethyl)ethyl-4-methylthiazol-2-ylamine] for iNOS was similar to that of oxazolidine derivative 1b (4-methyl-5-propyl-2-imino-1,3-oxazolidine) and much higher than that of L-NAME. However, we could not enhance the inhibitory activity against iNOS by introducing an alkyl substituent into the 2-aminothiazole ring as we could in the case of oxazolidine one. On the other hand, introduction of bulky or hydrophilic substituent at any position of the 2-aminothiazole ring remarkably decreased or even abolished the inhibitory activity against NOS.
authors.affiliation: Chemistry Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, 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: Motoji
authors.initials: M
authors.lastname: Kawasaki
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yano
authors.forename: Motoharu
authors.initials: M
authors.lastname: Ido
mesh_terms: D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008297:Male; D051379:Mice; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D013844:Thiazoles; C004483:2-aminothiazole; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat