Multi-dimensional target profiling of N,4-diaryl-1,3-thiazole-2-amines as potent inhibitors of eicosanoid metabolism

• Published in: European journal of medicinal chemistry Vol. 84; pp. 302 - 311
• Main Authors: Rödl, Carmen B., Vogt, Dominik, Kretschmer, Simon B.M., Ihlefeld, Katja, Barzen, Sebastian, Brüggerhoff, Astrid, Achenbach, Janosch, Proschak, Ewgenij, Steinhilber, Dieter, Stark, Holger, Hofmann, Bettina
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 12.09.2014; Elsevier
• Subjects: 5-Lipoxygenase; 5-Lipoxygenase-Activating Proteins - metabolism; Aminophenols - chemical synthesis; Aminophenols - chemistry; Aminophenols - pharmacology; Cancer; Cardiovascular diseases; Chemistry, Medicinal; Cyclooxygenase; Cyclooxygenase 2 - metabolism; Dose-Response Relationship, Drug; Eicosanoids - antagonists & inhibitors; Eicosanoids - metabolism; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; HeLa Cells; Humans; Inflammation; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; Thiazole-2-amines; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Tumor Cells, Cultured; U937 Cells; AA; H(P)ETE; SAR; Thiazole-2-amines; Inflammation; (5-)LO; COX; LDH; Cyclooxygenase; TXA2; LT(B4); NDGA; NSAIDs; 5-Lipoxygenase; PG; 12-HHT; Cardiovascular diseases; PMNL; Cancer; SELECTIVE-INHIBITION; CYCLOOXYGENASE-2; SPHINGOSINE KINASE 1; TUMOR-CELLS; ARACHIDONIC-ACID; DISCOVERY; 5-LIPOXYGENASE INHIBITORS; IN-VIVO; DUAL INHIBITORS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.07.025

Eicosanoids like leukotrienes and prostaglandins play a considerable role in inflammation. Produced within the arachidonic acid (AA) cascade, these lipid mediators are involved in the pathogenesis of pain as well as acute and chronic inflammatory diseases like rheumatoid arthritis and asthma. With regard to the lipid cross-talk within the AA pathway, a promising approach for an effective anti-inflammatory therapy is the development of inhibitors targeting more than one enzyme of this cascade. Within this study, thirty N-4-diaryl-1,3-thiazole-2-amine based compounds with different substitution patterns were synthesized and tested in various cell-based assays to investigate their activity and selectivity profile concerning five key enzymes involved in eicosanoid metabolism (5-, 12-, 15-lipoxygenase (LO), cyclooxygenase-1 and -2 (COX-1/-2)). With compound 7, 2-(4-phenyl)thiazol-2-ylamino)phenol (ST-1355), a multi-target ligand targeting all tested enzymes is presented, whereas compound 9, 2-(4-(4-chlorophenyl)thiazol-2-ylamino)phenol (ST-1705), represents a potent and selective 5-LO and COX-2 inhibitor with an IC50 value of 0.9 ± 0.2 μM (5-LO) and a residual activity of 9.1 ± 1.1% at 10 μM (COX-2 product formation). The promising characteristics and the additional non-cytotoxic profile of both compounds reveal new lead structures for the treatment of eicosanoid-mediated diseases. [Display omitted] •N,4-Diaryl-1,3-thiazole-2-amines are promising anti-inflammatory agents.•Multi-target interference in the arachidonic acid cascade could avoid lipid crosstalk.•2-(4-Phenyl)thiazol-2-ylamino)phenol (ST-1355) inhibits all tested enzymes.•2-(4-(4-Chlorophenyl)thiazol-2-ylamino)phenol (ST-1705) is a dual 5-LO/COX-2 inhibitor.•ST-1355 and ST-1705 are new non-cytotoxic lead compounds for eicosanoid-mediated diseases.