Design, synthesis, and X-ray structure of potent memapsin 2 (β-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands
Design, synthesis, and X-ray structure of potent memapsin 2 (β-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands
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DOI：
10.1021/jm061338s
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发表时间：
2007-05-17
影响因子：
7.3
通讯作者：
Tang, Jordan
中科院分区：
文献类型：
--
作者：
Ghosh, Arun K.;Kumaragurubaran, Nagaswamy;Tang, Jordan
基于结构的设计和合成的一些有效的和选择性的memapsin 2抑制剂的描述。这些抑制剂是基于膜蛋白酶2结合的抑制剂3的X射线结构设计的，该抑制剂3包含甲磺酰基丙氨酸作为P-2-配体和取代的吡唑作为P-3-配体。特别重要的是，我们研究了取代的天冬酰胺衍生物的能力，以模拟3结合的memapsin 2的酶活性位点的S-2-S-3区域中的关键相互作用。我们研究了各种取代的苯乙基，α-甲基苄基，和恶唑甲基基团作为P-3-配体。许多抑制剂对mempasin 2表现出非常有效的抑制活性，对memapsin 1表现出良好的选择性。抑制剂5d显示出低纳摩尔酶抑制效力（Ki = 1.1 nM）和非常好的细胞抑制活性（IC 50 = 39 nM）。此外，在一项初步研究中，抑制剂5d在单次腹膜内给药（8 mg/kg）后显示转基因小鼠中A β（40）的产生减少30%。5d结合的memapsin 2的蛋白质-配体X射线晶体结构提供了重要的分子见解，可以作为进一步设计新型抑制剂的重要指导。
Structure-based design and synthesis of a number of potent and selective memapsin 2 inhibitors are described. These inhibitors were designed based upon the X-ray structure of memapsin 2-bound inhibitor 3 that incorporates methylsulfonyl alanine as the P-2-ligand and a substituted pyrazole as the P-3-ligand. Of particular importance, we examined the ability of the substituted isophthalic acid amide derivative to mimic the key interactions in the S-2-S-3 regions of the enzyme active sites of 3-bound memapsin 2. We investigated various substituted phenylethyl, alpha-methylbenzyl, and oxazolylmethyl groups as the P-3-ligands. A number of inhibitors exhibited very potent inhibitory activity against mempasin 2 and good selectivity against memapsin 1. Inhibitor 5d has shown low nanomolar enzyme inhibitory potency (K-i = 1.1 nM) and very good cellular inhibitory activity (IC50 = 39 nM). Furthermore, in a preliminary study, inhibitor 5d has shown 30% reduction of A beta(40) production in transgenic mice after a single intraperitoneal administration (8 mg/kg). A protein-ligand X-ray crystal structure of 5d-bound memapsin 2 provided vital molecular insight that can serve as an important guide to further design of novel inhibitors.