Discovery of (S)-N-(2-Amino-4-fluorophenyl)-4-(1-(3-(4-((dimethylamino)methyl)phenyl)-6-oxopyridazin-1(6H)-yl)ethyl)benzamide as Potent Class I Selective HDAC Inhibitor for Oral Anticancer Drug Candidate,Journal of Medicinal Chemistry

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Discovery of (S)-N-(2-Amino-4-fluorophenyl)-4-(1-(3-(4-((dimethylamino)methyl)phenyl)-6-oxopyridazin-1(6H)-yl)ethyl)benzamide as Potent Class I Selective HDAC Inhibitor for Oral Anticancer Drug Candidate
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-05-15 , DOI: 10.1021/acs.jmedchem.3c00525
Daqiang Li ₁ , Zhuo Zhang _{1,

2,

3} , Yalei Li ₄ , Xinyi Wang _{3,

4} , Hanyue Zhong _{1,

3} , Huajie Yang ₁ , Yong Xi ₄ , Hongchun Liu ₄ , Aijun Shen _{3,

4,

5} , Youhong Hu _{1,

2,

3,

6}

Affiliation

A novel series of benzamide derivatives were successively designed and synthesized prepared from the pyridazinone scaffold. Among them, (S)-17b, demonstrated potent inhibitory activity in vitro toward human class I HDAC isoforms and human myelodysplastic syndrome (SKM-1) cell line. Also, (S)-17b strongly increased the intracellular level of acetyl-histone H3 and P21 simultaneously and effectively induced G1 cell cycle arrest and apoptosis. Through oral dosing in SKM-1 xenograft models, (S)-17b exhibited excellent in vivo antitumor activity. In addition, compound (S)-17b showed better antitumor efficacy on mouse models with intact immune system than those with thymus deficiencies. Furthermore, this compound displayed a favorable pharmacokinetic profile in ICR mice and SD rat, respectively, minimal metabolic property differences among hepatocytes from five species, and a low inhibition upon the human ether-a-go-go (hERG) channel with an IC₅₀ value of 34.6 μΜ. This novel compound (S)-17b may serve as a new drug candidate for further investigation.

中文翻译：

(S)-N-(2-氨基-4-氟苯基)-4-(1-(3-(4-((二甲氨基)甲基)苯基)-6-氧代哒嗪-1(6H)-基)乙基的发现) 苯甲酰胺作为口服抗癌候选药物的有效 I 类选择性 HDAC 抑制剂

以哒嗪酮骨架为基础，相继设计并合成了一系列新型苯甲酰胺衍生物。其中，( S ) -17b在体外对人I类HDAC亚型和人骨髓增生异常综合征(SKM-1)细胞系表现出有效的抑制活性。此外，( S ) -17b同时强烈增加细胞内乙酰组蛋白 H3 和 P21 的水平，并有效诱导 G1 细胞周期停滞和凋亡。通过在SKM-1异种移植模型中口服给药，( S ) -17b表现出优异的体内抗肿瘤活性。另外，化合物( S ) -17b在免疫系统完整的小鼠模型上显示出比胸腺缺陷的小鼠模型更好的抗肿瘤功效。此外，该化合物分别在 ICR 小鼠和 SD 大鼠中表现出良好的药代动力学特征，五个物种的肝细胞之间的代谢特性差异极小，并且对人 ether-a-go-go (hERG) 通道具有较低的抑制作用，IC ₅₀值为34.6μM。这种新型化合物( S ) -17b可作为进一步研究的新候选药物。

更新日期：2023-05-15

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