期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 19, 期 11, 页码 3394-3401出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2011.04.034
关键词
5-Lipoxygenase; Leukotriene; Neutrophils; Inflammation; Prostaglandin
资金
- Carl-Zeiss
5-Lipoxygenase (5-LO) and microsomal prostaglandin E-2 synthase (mPGES)-1 are key enzymes in the biosynthesis of leukotrienes and prostaglandin (PG)E-2, respectively, and are considered as valuable targets for the treatment of inflammatory diseases. Here, we present the identification of 2-mercaptohexanoic acid derivatives as dual inhibitors of 5-LO and mPGES-1. The lead compound 2(4-(3-biphenyloxypropoxy) phenylthio) hexanoic acid (21) inhibits human 5-LO and mPGES-1 in cell-free assays with an IC50 = 3.5 and 2.2 mu M, respectively, and suppresses 5-LO in intact cells with even a higher potency (IC50 = 0.9 mu M). Compound 21 (10 mu M) neither significantly inhibited the related 12- or 15-LOs nor cyclooxygenase-1 and -2 or cytosolic phospholipase A(2). Based on the selective and potent inhibition of 5-LO and mPGES-1, further assessment of these 2-mercaptohexanoic acids in preclinical models of inflammation are warranted. (C) 2011 Elsevier Ltd. All rights reserved.
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