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Development of novel aminothiazole-comprising 5-LO inhibitors

: Kretschmer, S.B.M.; Woltersdorf, S.; Rödl, C.B.; Vogt, D.; Häfner, A.-K.; Steinhilber, D.; Stark, H.; Hofmann, B.


Future medicinal chemistry 8 (2016), No.2, pp.149-164
ISSN: 1756-8927
ISSN: 1756-8919
Journal Article
Fraunhofer IME ()

Background: Leukotrienes are pivotal lipid mediators in various immune and inflammatory reactions. Herein, 5-LO is a validated target. 2-Aminothiazoles, as a privileged structure, implicate known 5-LO inhibitors like ST-1083 (IC50 [polymorphonuclear leukocytes (PMNL)] = 0.68 μM), yet deep structure–activity relationships (SAR) have not been established. Materials & methods: Compounds were synthesized via Hantzsch thiazole synthesis. Inhibitory activities were evaluated using intact PMNL and purified 5-LO together with cytotoxicity measurements in U937 cells. Results: We introduced novel functionalities at 2-, 3-, 4- and 5-position of the 2-aminothiazole scaffold and conducted bioisosteric replacement to optimize the parent scaffold. SARs of the 2-aminothiazole scaffold were deduced and extended primarily for inhibition of the 5-LO enzyme. Conclusion: SAR studies provided at least two optimized leads (ST-1853, ST-1906) with high potency (IC50 [polymorphonuclear leukocytes] = 0.05 μM), specificity and noncytotoxic behavior.