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Selective Inhibitors of Human Neuraminidase 3
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-02-09 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01574 Tianlin Guo 1 , Philipp Dätwyler 2 , Ekaterina Demina 3 , Michele R. Richards 1 , Peng Ge 1 , Chunxia Zou 1 , Ruixiang Zheng 1 , Anne Fougerat 3 , Alexey V. Pshezhetsky 3 , Beat Ernst 2 , Christopher W. Cairo 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-02-09 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01574 Tianlin Guo 1 , Philipp Dätwyler 2 , Ekaterina Demina 3 , Michele R. Richards 1 , Peng Ge 1 , Chunxia Zou 1 , Ruixiang Zheng 1 , Anne Fougerat 3 , Alexey V. Pshezhetsky 3 , Beat Ernst 2 , Christopher W. Cairo 1
Affiliation
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Human neuraminidases (NEU) are associated with human diseases including cancer, atherosclerosis, and diabetes. To obtain small molecule inhibitors as research tools for the study of their biological functions, we designed a library of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) analogues with modifications at C4 and C9 positions. This library allowed us to discover selective inhibitors targeting the human NEU3 isoenzyme. Our most selective inhibitor for NEU3 has a Ki of 320 ± 40 nM and a 15-fold selectivity over other human neuraminidase isoenzymes. This inhibitor blocks glycolipid processing by NEU3 in vitro. To improve their pharmacokinetic properties, various esters of the best inhibitors were synthesized and evaluated. Finally, we confirmed that our best compounds exhibited selective inhibition of NEU orthologues from murine brain.
中文翻译：
人类神经氨酸酶3的选择性抑制剂
人神经氨酸酶（NEU）与人类疾病有关，包括癌症，动脉粥样硬化和糖尿病。为了获得作为研究其生物学功能的研究工具的小分子抑制剂，我们设计了一个在C4和C9位置进行了修饰的2-deoxy-2,3-didehydro- N - acetylneuraminic acid（DANA）类似物库。该文库使我们能够发现针对人NEU3同工酶的选择性抑制剂。我们对NEU3最具选择性的抑制剂具有K i比其他人类神经氨酸酶同工酶具有320±40 nM的选择性和15倍的选择性。该抑制剂在体外阻断NEU3对糖脂的加工。为了改善它们的药代动力学特性，合成并评估了最佳抑制剂的各种酯。最后，我们证实了我们最好的化合物对鼠脑中的NEU直向同源物表现出选择性抑制作用。
更新日期：2018-02-09
中文翻译：
人类神经氨酸酶3的选择性抑制剂
人神经氨酸酶（NEU）与人类疾病有关，包括癌症，动脉粥样硬化和糖尿病。为了获得作为研究其生物学功能的研究工具的小分子抑制剂，我们设计了一个在C4和C9位置进行了修饰的2-deoxy-2,3-didehydro- N - acetylneuraminic acid（DANA）类似物库。该文库使我们能够发现针对人NEU3同工酶的选择性抑制剂。我们对NEU3最具选择性的抑制剂具有K i比其他人类神经氨酸酶同工酶具有320±40 nM的选择性和15倍的选择性。该抑制剂在体外阻断NEU3对糖脂的加工。为了改善它们的药代动力学特性，合成并评估了最佳抑制剂的各种酯。最后，我们证实了我们最好的化合物对鼠脑中的NEU直向同源物表现出选择性抑制作用。
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