Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitors

被引：16

作者：

Liu, Gang ^{[1
]}

Abraham, Sunny ^{[1
]}

Liu, Xing ^{[1
]}

Xu, Shimin ^{[1
]}

Rooks, Allison M. ^{[2
]}

Nepomuceno, Ron ^{[2
]}

Dao, Alan ^{[2
]}

Brigham, Daniel ^{[2
]}

Gitnick, Dana ^{[3
]}

Insko, Darren E. ^{[3
]}

Gardner, Michael F. ^{[3
]}

Zarrinkar, Patrick P. ^{[4
]}

Christopher, Ron ^{[3
]}

Belli, Barbara ^{[2
]}

Armstrong, Robert C. ^{[2
]}

Holladay, Mark W. ^{[1
]}

机构：

[1] Ambit Biosci Corp, Dept Med Chem, San Diego, CA 92121 USA

[2] Ambit Biosci Corp, Cell Biol & Pharmacol, San Diego, CA 92121 USA

[3] Ambit Biosci Corp, DMPK & Toxicol, San Diego, CA 92121 USA

[4] Ambit Biosci Corp, Technol Dev, San Diego, CA 92121 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 17期

关键词：

Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3); Aminopyridine; Hinge binding motif; CYP3A4; Time-dependent inhibition; THERAPEUTIC TARGET; MUTATIONS; MECHANISM; LEUKEMIA; RAF;

D O I：

10.1016/j.bmcl.2015.07.023

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Based on a putative binding mode of quizartinib (AC220, 1), a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor in Phase III clinical development, we have designed de novo a simpler aminopyridine-based hinge binding motif. Further optimization focusing on maximizing in vivo efficacy and minimizing CYP3A4 time-dependent inhibition resulted in a highly efficacious compound (6s) in tumor xenograft model for further preclinical development. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：3436 / 3441

页数：6

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