Aminothiazole-Featured Pirinixic Acid Derivatives As Dual 5-Lipoxygenase and Microsomal Prostaglandin E2 Synthase-1 Inhibitors with Improved Potency and Efficiency in Vivo

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• 作者：Thomas Hanke ; Friederike Dehm ; Stefanie Liening ; Sven-Desiderius Popella ; Jonas Maczewsky ; Max Pillong ; Jens Kunze ; Christina Weinigel ; Dagmar Barz ; Astrid Kaiser ; Mario Wurglics ; Michael L盲mmerhofer ; Gisbert Schneider ; Lidia Sautebin ; Manfred Schubert-Zsilavecz ; Oliver Werz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 27, 2013
• 年：2013
• 卷：56
• 期：22
• 页码：9031-9044
• 全文大小：621K
• 年卷期：v.56,no.22(November 27, 2013)
• ISSN：1520-4804

文摘

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 渭M, 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 渭M) 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.