Development of novel aminothiazole-comprising 5-LO inhibitors
| Autor: | Stefano Woltersdorf, Dominik Vogt, Holger Stark, Simon B.M. Kretschmer, Ann-Kathrin Häfner, Bettina Hofmann, Dieter Steinhilber, Carmen B. Rödl |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cell Survival Stereochemistry 01 natural sciences Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Aminothiazole Drug Discovery Humans Structure–activity relationship Lipoxygenase Inhibitors Cytotoxicity IC50 Cells Cultured Pharmacology chemistry.chemical_classification Arachidonate 5-Lipoxygenase U937 cell biology 010405 organic chemistry Lipid signaling 0104 chemical sciences Thiazoles 030104 developmental biology Enzyme chemistry Biochemistry Drug Design Arachidonate 5-lipoxygenase Leukocytes Mononuclear biology.protein Molecular Medicine |
| Zdroj: | Future Medicinal Chemistry. 8:149-164 |
| ISSN: | 1756-8927 1756-8919 |
| DOI: | 10.4155/fmc.15.174 |
| Popis: | 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. [Formula: see text] |
| Databáze: | OpenAIRE |
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