化学
抗血栓
生物利用度
体内
药理学
小分子
磺胺
组合化学
铅化合物
配体(生物化学)
砜
立体化学
体外
生物化学
受体
医学
有机化学
心脏病学
生物技术
生物
作者
Susanne Roehrig,Alexander Straub,Jens Pohlmann,Thomas Lampe,Josef Pernerstorfer,Karl‐Heinz Schlemmer,Peter Reinemer,Elisabeth Perzborn
摘要
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.
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