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Aminothiazole-Featured Pirinixic Acid Derivatives As Dual 5-Lipoxygenase and Microsomal Prostaglandin E 2 Synthase-1 Inhibitors with Improved Potency and Efficiency in Vivo

2013; American Chemical Society; Volume: 56; Issue: 22 Linguagem: Inglês

10.1021/jm401557w

1520-4804

Thomas Hanke, Friederike Dehm, Stefanie Liening, Sven-Desiderius Popella, Jonas Maczewsky, Max Pillong, Jens Kunze, Christina Weinigel, Dagmar Barz, Astrid Kaiser, Mario Wurglics, Michael Lämmerhofer, Gisbert Schneider, Lidia Sautebin, Manfred Schubert‐Zsilavecz, Oliver Werz,

Synthesis and biological activity

Dual inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) is currently pursued as potential pharmacological strategy for treatment of inflammation and cancer. Here we present a series of 26 novel 2-aminothiazole-featured pirinixic acid derivatives as dual 5-LO/mPGES-1 inhibitors with improved potency (exemplified by compound 16 (2-[(4-chloro-6-{[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic acid) with IC50 = 0.3 and 0.4 μM, respectively) and bioactivity in vivo. Computational analysis presumes binding sites of 16 at the tip of the 5-LO catalytic domain and within a subpocket of the mPGES-1 active site. Compound 16 (10 μM) hardly suppressed cyclooxygenase (COX)-1/2 activities, failed to inhibit 12/15-LOs, and is devoid of radical scavenger properties. Finally, compound 16 reduced vascular permeability and inflammatory cell infiltration in a zymosan-induced mouse peritonitis model accompanied by impaired levels of cysteinyl-leukotrienes and prostaglandin E2. Together, 2-aminothiazole-featured pirinixic acids represent potent dual 5-LO/mPGES-1 inhibitors with an attractive pharmacological profile as anti-inflammatory drugs.