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 IC: 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.
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| http://dx.doi.org/10.1016/j.bmcl.2024.129610 | DOI Listing |
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Design, synthesis and biological evaluation of 6-chloro-quinolin-2-one derivatives as novel FXIa inhibitors.
Bioorg Med Chem Lett
February 2024
Tianjin Key Laboratory of Molecular Design and Drug Discovery, Puchuang Pharmaceutical Technology (Tianjin) Co., Ltd, Tianjin Institute of Pharmaceutical Research, 306 Huiren Road, Tianjin 300301, PR China; National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Institute of Pharmaceutical Research, 306 Huiren Road, Tianjin 300301, PR China. Electronic address:
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 IC: 15 nM, 2 x aPTT: 6.
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