Design, Synthesis, and Structure-Activity and Structure-Pharmacokinetic Relationship Studies of Novel [6,6,5] Tricyclic Fused Oxazolidinones Leading to the Discovery of a Potent, Selective, and Orally Bioavailable FXa Inhibitor
Design, Synthesis, and Structure-Activity and Structure-Pharmacokinetic Relationship Studies of Novel [6,6,5] Tricyclic Fused Oxazolidinones Leading to the Discovery of a Potent, Selective, and Orally Bioavailable FXa Inhibitor
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新型 [6,6,5] 三环稠合恶唑烷酮的设计、合成以及结构-活性和结构-药代动力学关系研究导致发现了一种有效的、选择性的、口服生物可利用的 FXa 抑制剂
DOI：
10.1021/jm501045e
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发表时间：
2014-09-25
影响因子：
7.3
通讯作者：
Yang, Yushe
中科院分区：
文献类型：
--
作者：
Xue, Tao;Ding, Shi;Yang, Yushe
凝血酶Xa(FXA)是一种特别有前景的抗凝治疗靶点，寻找口服FXA小分子抑制剂仍是研究热点。基于FXA及其抑制剂利伐沙班的X-射线晶体结构，我们设计合成了一系列构象受限的新型[6，6，5]三环稠恶唑烷酮类支架。对这一新系列进行了密集的结构-活性关系(SAR)和结构-药代动力学关系(SPR)研究，发现了化合物11a：一种高效、选择性、直接和口服生物利用的FXA抑制剂，具有良好的体内抗血栓效果和良好的药代动力学特征。对化合物11a进行了可药性评价，得出了积极的结果。所有结果表明，化合物11a是预防和治疗静脉和动脉系统血栓栓塞性疾病的有前途的候选药物。
The blood coagulation enzyme factor Xa (FXa) is a particularly promising target for anticoagulant therapy, and identification of oral small-molecule inhibitors of FXa remains a research focus. On the basis of the X-ray crystal structure of FXa and its inhibitor rivaroxaban, we designed and synthesized a series of conformationally restricted mimics containing a novel [6,6,5] tricyclic fused oxazolidinone scaffold. Intensive structure-activity relationship (SAR) and structure-pharmacokinetic relationship (SPR) studies on this new series led to the discovery of compound 11a: a highly potent, selective, direct, and orally bioavailable FXa inhibitor with excellent in vivo antithrombotic efficacy and preferable pharmacokinetic profiles. Druggability evaluation of compound 11a was undertaken and elicited positive outcomes. All results indicate that compound 11a is a promising drug candidate for the prevention and treatment of thromboembolic diseases in venous and arterial systems.