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Novel, Self-Assembling Dimeric Inhibitors of Human β Tryptase.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-02-14 , DOI: 10.1021/acs.jmedchem.9b01689
Sarah F Giardina 1 , Douglas S Werner 2 , Maneesh Pingle 1, 2 , Philip B Feinberg 1 , Kenneth W Foreman 2 , Donald E Bergstrom 3 , Lee D Arnold 2 , Francis Barany 1
Affiliation  

β-Tryptase, a homotetrameric serine protease, has four identical active sites facing a central pore, presenting an optimized setting for the rational design of bivalent inhibitors that bridge two adjacent sites. Using diol, hydroxymethyl phenols or benzoyl methyl hydroxamates, and boronic acid chemistries to reversibly join two [3-(1-acylpiperidin-4-yl)phenyl]methanamine core ligands, we have successfully produced a series of self-assembling heterodimeric inhibitors. These heterodimeric tryptase inhibitors demonstrate superior activity compared to monomeric modes of inhibition. X-ray crystallography validated the dimeric mechanism of inhibition, and compounds demonstrated high selectivity against related proteases, good target engagement, and tryptase inhibition in HMC1 xenograft models. Screening 3872 possible combinations from 44 boronic acid and 88 diol derivatives revealed several combinations that produced nanomolar inhibition, and seven unique pairs produced greater than 100-fold improvement in potency over monomeric inhibition. These heterodimeric tryptase inhibitors demonstrate the power of target-driven combinatorial chemistry to deliver bivalent drugs in a small molecule form.

中文翻译:

人β类胰蛋白酶的新型,自组装二聚体抑制剂。

β-色氨酸酶是一种同四聚体丝氨酸蛋白酶,具有面对中央孔的四个相同的活性位点,为桥接两个相邻位点的二价抑制剂的合理设计提供了优化的环境。使用二醇,羟甲基苯酚或苯甲酰基甲基异羟肟酸酯,以及硼酸化学方法可逆地连接两个[3-(1-酰基哌啶丁-4-基)苯基]甲胺核心配体,我们成功生产了一系列自组装的异二聚抑制剂。与单体抑制模式相比,这些异二聚体类胰蛋白酶抑制剂具有更高的活性。X射线晶体学验证了抑制作用的二聚体机制,并且化合物在HMC1异种移植模型中显示出对相关蛋白酶的高选择性,良好的靶标结合和类胰蛋白酶抑制作用。从44种硼酸和88种二醇衍生物中筛选了3872种可能的组合,发现了产生纳摩尔抑制作用的几种组合,而七对独特的组合产生的效能比单体抑制作用提高了100倍以上。这些异二聚体类胰蛋白酶抑制剂证明了目标驱动的组合化学以小分子形式递送二价药物的能力。
更新日期:2020-02-27
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