Uses
Microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) are key enzymes in the synthesis of PGE2 and leukotrienes (LTs), respectively. PGE2 and LTs are bioactive lipids that contribute to a broad range of pathologies, including inflammation and various forms of cancer. Pirinixic acid aminothiazole is a dual inhibitor of mPGES-1 and 5-LO (IC50s = 0.4 and 0.2 μM, respectively). It is a weak inhibitor of COX-1 and -2 and has no effect on 12- and 15-LO isoforms. Pirinixic acid aminothiazole reduces the synthesis of PGE2 and LTC4 during zymosan-induced peritonitis in mice, resulting in a significantly diminished inflammatory response.[Cayman Chemical]
Biological Activity
pirinixic acid aminothiazole is a dual inhibitor of 5-lipoxygenase (5-lo) and microsomal prostaglandin e2 synthase 1 (mpges-1) with ic50 values of 0.3 and 0.4 μm, respectively [1].5-lipoxygenase (5-lo) and microsomal prostaglandin e2 synthase-1 (mpges-1) are critical enzymes involved in the metabolism of arachidonic acid (aa). they are key enzymes in the synthesis of leukotrienes (lts) and pge2, respectively [1][2][3]. dual inhibition of 5-lo and mpges-1 is currently pursued as potential pharmacological strategy for treatment of inflammation and cancer [1].pirinixic acid aminothiazole is a dual inhibitor of 5-lo and mpges-1. pirinixic acid aminothiazole hardly inhibited cyclooxygenase (cox)-1/2 activities and failed to inhibit 12/15-los. in cell-free assay, pirinixic acid aminothiazole was highly potent against both 5-lo and mpges-1 with ic50 values of 0.3 and 0.4 μm, respectively. in the cell-based assay, pirinixic acid aminothiazole inhibited 5-lo directly with ic50 value of 0.2 μm [1].in zymosan-induced peritonitis in mice, pirinixic acid aminothiazole (10 mg/kg) reduced vascular permeability by 57% and inhibited neutrophil infiltration by 45%, accompanied by significantly impaired levels of cyslts (84% reduction) and pge2 (46% reduction). these results suggested that pirinixic acid aminothiazole dually inhibited lt and pge2 synthesis in vivo connected to anti-inflammatory effectiveness [1].
in vivo
5-LO/mPGES1-IN-1 (10 mg/kg, intraperitoneally injected, pretreated 30 minutes before peritonitis induction) reduces vascular permeability and inflammatory cell infiltration in zymosan-induced mouse peritonitis models. Impaired cysteine-leukotriene and prostaglandin E2 levels[1].
| Animal Model: | Zymosan-Induced Peritonitis in Mice[1] |
| Dosage: | 10 mg/kg |
| Administration: | i.p. pretreated 30 minutes before peritonitis induction |
| Result: | Reduced vascular permeability by 57% and inhibited neutrophil infiltration by 45%. |
IC 50
5-LOX: 0.4 μM (IC50)
References
[1]. hanke t, dehm f, liening s, et al. aminothiazole-featured pirinixic acid derivatives as dual 5-lipoxygenase and microsomal prostaglandin e2 synthase-1 inhibitors with improved potency and efficiency in vivo. j med chem. 2013 nov 27;56(22):9031-44.
[2]. funk cd. prostaglandins and leukotrienes: advances in eicosanoid biology. science. 2001 nov 30;294(5548):1871-5.
[3]. samuelsson b, morgenstern r, jakobsson pj. membrane prostaglandin e synthase-1: a novel therapeutic target. pharmacol rev. 2007 sep;59(3):207-24.
