Abstract：
A series of 6-chloro-quinolin-2-one derivatives were designed and synthesized as FXIa inhibitors by exploration of P1, P1 prime and P2 prime groups. Each compound was accessed for inhibitory effect on FXIa and some of them were evaluated in the clotting assay. 14c demonstrated excellent in-vitro potency (FXIa IC50: 15 nM, 2 x aPTT: 6.8 μM) and good in-vivo efficacy (prolonged in-vivo aPTT by more than 1-fold but not PT). Moreover, the pharmacokinetics property of 14c were evaluated following intravenous administration in rats, which indicated that 14c probably will be a clinical candidate for intravenous administration.
摘要：
通过探索P1，P1prime和P2prime基团，设计并合成了一系列6-氯-喹啉-2-酮衍生物作为FXIa抑制剂。获取每种化合物对FXIa的抑制作用,并在凝血测定中评价它们中的一些。14c表现出优异的体外效力(FXIaIC50：15nM，2×aPTT：6.8μM）和良好的体内功效（体内aPTT延长了1倍以上，但不是PT）。此外，14c的药代动力学特性在大鼠静脉给药后进行评估，这表明14c可能是静脉给药的临床候选药物。
