Synthesis and biological evaluation of N-(3-fluorobenzyl)-4-(1-(methyl-d3)-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-amine as a novel, potent ALK5 receptor inhibitor

被引：1

作者：

Kang, Byung-Nam ^{[1
,2
]}

Kang, Hong-Jun ^{[1
]}

Kim, Sunjoo ^{[1
]}

Lee, Jungwoo ^{[1
]}

Lee, Jinwoo ^{[1
]}

Jeong, Hee-Jin ^{[1
]}

Jeon, Seeun ^{[1
]}

Shin, Youngdo ^{[1
]}

Yoon, Cheolhwan ^{[1
]}

Han, Cheolkyu ^{[1
,3
]}

Seo, Jeongbeob ^{[1
]}

Yun, Jaesook ^{[2
]}

机构：

[1] BiSiChem, 3F Pangyo Ro,255 Beon Gil 74, Seongnam, South Korea

[2] Sungkyunkwan Univ, Dept Chem, Suwon 16419, South Korea

[3] Catholic Univ Korea, Dept Med & Biosci, Bucheon 14662, South Korea

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2023年 / 85卷

关键词：

TGF-; ALK5; inhibitor; Cytochrome P-450 (CYP) inhibitor; Deuterium; BETA; DEUTERIUM;

D O I：

10.1016/j.bmcl.2023.129205

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Specific inhibition of ALK5 provides a novel method for controlling the development of cancers and fibrotic diseases. In this work, a novel series of N-(3-fluorobenzyl)-4-(1-(methyl-d3)-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-amine (11), a potential clinical candidate, was synthesized by strategic incorporation deuterium at potential metabolic soft spots and identified as ALK5 inhibitors. This compound has a low potential for CYP-mediated drug-drug interactions as a CYP450 inhibitor (IC50 = >10 mu M) and showed potent inhibitory effects in cellular assay (IC50 = 3.5 +/- 0.4 nM). The pharmacokinetic evaluation of 11 in mice demonstrated moderate clearance (29.0 mL/min/kg) and also revealed high oral bioavailability in mice (F = 67.6%).

引用

页数：7

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