Despite recent progress in antithrombotic therapy, there is still an unmet medical need for safe and orally available anticoagulants. The coagulation enzyme Factor Xa (FXa) is a particularly promising target, and recent efforts in this field have focused on the identification of small-molecule inhibitors with good oral bioavailability. We identified oxazolidinone derivatives as a new class of potent FXa inhibitors. Lead optimization led to the discovery of BAY 59-7939 (5), a highly potent and selective, direct FXa inhibitor with excellent in vivo antithrombotic activity. The X-ray crystal structure of 5 in complex with human FXa clarified the binding mode and the stringent requirements for high affinity. The interaction of the neutral ligand chlorothiophene in the S1 subsite allows for the combination of good oral bioavailability and high potency for nonbasic 5. Compound 5 is currently under clinical development for the prevention and treatment of thromboembolic diseases.

中文翻译：

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新型抗血栓药5-氯-N-（{（5S）-2-oxo-3- [4-（3-氧吗啉-4-基）苯基] -1,3-恶唑烷-5-基}甲基的发现噻吩-2-甲酰胺（BAY 59-7939）：一种口服直接Xa抑制剂。

尽管抗血栓治疗最近取得了进展，但对安全和口服抗凝剂的医疗需求仍未得到满足。凝血酶Xa因子（FXa）是一个特别有希望的目标，并且该领域的最新工作集中于鉴定具有良好口服生物利用度的小分子抑制剂。我们确定恶唑烷酮衍生物为一类新的有效FXa抑制剂。铅的优化导致发现了BAY 59-7939（5），BAY 59-7939（5）是一种高效的，选择性的，直接的FXa抑制剂，具有出色的体内抗血栓形成活性。与人FXa配合使用的X射线晶体结构5阐明了结合模式和对高亲和力的严格要求。