设计、合成及 6-氯-2-（喹啉-4-基）-1H-异喹啉-1,3（2H）-二酮衍生物作为新型 FXIa 抑制剂的生物评价。

Design, synthesis and biological evaluation of 6-chloro-quinolin-2-one derivatives as novel FXIa inhibitors.

机构信息

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.

出版信息

Bioorg Med Chem Lett. 2024 Feb 1;99:129610. doi: 10.1016/j.bmcl.2024.129610. Epub 2024 Jan 9.

DOI:10.1016/j.bmcl.2024.129610

PMID:38211702

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 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.

摘要

设计并合成了一系列 6-氯-2-（喹啉-4-酮）衍生物作为 FXIa 抑制剂，通过对 P1、P1’和 P2’基团的探索。对每个化合物进行了对 FXIa 的抑制作用评估，其中一些化合物进行了凝血测定。14c 表现出优异的体外活性（FXIa IC：15 nM，2 x aPTT：6.8 μM）和良好的体内疗效（体内 aPTT 延长超过 1 倍，但不影响 PT）。此外，还在大鼠体内静脉给药后评估了 14c 的药代动力学特性，这表明 14c 可能成为静脉给药的临床候选药物。