硫代二氢喹唑啉酮化合物作为髓过氧化物酶的新型抑制剂
Thioxo-dihydroquinazolin-one Compounds as Novel Inhibitors of Myeloperoxidase.
作者信息
Li Yang, Ganesh Thota, Diebold Becky A, Zhu Yerun, McCoy James W, Smith Susan M E, Sun Aiming, Lambeth J David
机构信息
Department of Pathology and Laboratory Medicine, Emory University , Atlanta, Georgia 30322, United States.
Department of Pharmacology, Emory University , Atlanta, Georgia 30322, United States.
出版信息
ACS Med Chem Lett. 2015 Aug 31;6(10):1047-52. doi: 10.1021/acsmedchemlett.5b00287. eCollection 2015 Oct 8.
Abstract
Myeloperoxidase (MPO) is a key antimicrobial enzyme, playing a normal role in host defense, but also contributing to inflammatory conditions including neuroinflammatory diseases such as Parkinson's and Alzheimer's. We synthesized and characterized more than 50 quinazolin-4(1H)-one derivatives and showed that this class of compounds inhibits MPO with IC50 values as low as 100 nM. Representative compounds showed partially reversible inhibition that was competitive with respect to Amplex Red substrate and did not result in the accumulation of MPO Compound II. Members of this group show promise for therapeutic development for the treatment of diseases in which inflammation plays a pathogenic role.
摘要
髓过氧化物酶（MPO）是一种关键的抗菌酶，在宿主防御中发挥正常作用，但也会导致包括帕金森病和阿尔茨海默病等神经炎症性疾病在内的炎症状态。我们合成并表征了50多种喹唑啉-4(1H)-酮衍生物，结果表明这类化合物对MPO具有抑制作用，其半数抑制浓度（IC50）值低至100 nM。代表性化合物表现出部分可逆抑制作用，这种抑制作用相对于Amplex Red底物具有竞争性，且不会导致MPO复合二聚体的积累。该类化合物有望用于治疗炎症起致病作用的疾病的治疗开发。
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