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

作者：Hanke Thomas; Dehm Friederike; Liening Stefanie; Popella Sven Desiderius; Maczewsky Jonas; Pillong Max; Kunze Jens; Weinigel Christina; Barz Dagmar; Kaiser Astrid; Wurglics Mario; Laemmerhofer Michael; Schneider Gi**ert; Sautebin Lidia; Schubert Zsilavecz Manfred^*; Werz Oliver

来源：Journal of Medicinal Chemistry, 2013, 56(22): 9031-9044.

DOI：10.1021/jm401557w

Dual inhibition of microsomal prostaglandin E-2 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 mu 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 mu 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 E-2. Together, 2-aminothiazole-featured pirinixic acids represent potent dual 5-LO/mPGES-1 inhibitors with an attractive pharmacological profile as anti-inflammatory drugs.

• 出版日期2013-11-28