Discovery of novel, orally bioavailable phenylacetamide derivatives as multikinase inhibitors and in vivo efficacy study in hepatocellular carcinoma animal models

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-19 DOI:10.1016/j.bmcl.2024.129971

Debasis Das, Lingzhi Xie, Dandan Qiao, Jianhe Jia, Jian Hong

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Abstract

Hepatocellular carcinoma (HCC) is considered as one of the leading causes of death in liver disease patients. Several signal transduction pathways are involved in HCC pathogenesis. Multikinase inhibitors (MKIs) show beneficial effects for HCC and the FDA approved a few MKIs including sorafenib, lenvatinib for HCC treatments. Here, a novel series of phenylacetamide derivatives were designed, synthesized and evaluated as multikinase inhibitors. Several compounds showed nanomolar IC₅₀ values against FLT1, FLT3, FLT4, KDR, PDGFRα, PDGFRβ. The compounds were tested against human hepatocellular carcinoma (HCC), human colon adenocarcinoma and human gastric carcinoma cell lines. With favorable pharmacokinetics profiles, compound 12 and compound 14 were selected for in vivo efficacy studies in Hep3B mice models and demonstrated efficacious than sorafenib.

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发现新型口服苯乙酰胺衍生物作为多激酶抑制剂，并在肝细胞癌动物模型中进行体内药效研究。

肝细胞癌（HCC）被认为是导致肝病患者死亡的主要原因之一。多种信号转导通路参与了 HCC 的发病机制。多激酶抑制剂（MKIs）对 HCC 有益，美国 FDA 批准了一些 MKIs 用于 HCC 治疗，包括索拉非尼、来伐替尼。本文设计、合成并评估了一系列新型苯乙酰胺衍生物作为多激酶抑制剂。一些化合物对 FLT1、FLT3、FLT4、KDR、PDGFRα、PDGFRβ 的 IC50 值达到纳摩尔级。这些化合物针对人肝癌（HCC）、人结肠腺癌和人胃癌细胞系进行了测试。化合物 12 和化合物 14 具有良好的药代动力学特征，因此被选中在 Hep3B 小鼠模型中进行体内药效研究，结果表明其疗效优于索拉非尼。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.