Discovery of N-(4-(3-(2-Aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine (AMG 900), A Highly Selective, Orally Bioavailable Inhibitor of Aurora Kinases wi

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• 作者：Stephanie Geuns-Meyer ; Victor J. Cee ; Holly L. Deak ; Bingfan Du ; Brian L. Hodous ; Hanh Nho Nguyen ; Philip R. Olivieri ; Laurie B. Schenkel ; Karina R. Vaida ; Paul Andrews ; Annette Bak ; Xuhai Be ; Pedro J. Beltran ; Tammy L. Bush ; Mary K. Chaves ; Grace Chung ; Yang Dai ; Patrick Eden ; Kelly Hanestad ; Liyue Huang ; Min-Hwa Jasmine Lin ; Jin Tang ; Beth Ziegler ; Robert Radinsky ; Richard Kendall ; Vinod F. Patel ; Marc Payton
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：July 9, 2015
• 年：2015
• 卷：58
• 期：13
• 页码：5189-5207
• 全文大小：774K
• ISSN：1520-4804

文摘

Efforts to improve upon the physical properties and metabolic stability of Aurora kinase inhibitor 14a revealed that potency against multidrug-resistant cell lines was compromised by increased polarity. Despite its high in vitro metabolic intrinsic clearance, 23r (AMG 900) showed acceptable pharmacokinetic properties and robust pharmacodynamic activity. Projecting from in vitro data to in vivo target coverage was not practical due to disjunctions between enzyme and cell data, complex and apparently contradictory indicators of binding kinetics, and unmeasurable free fraction in plasma. In contrast, it was straightforward to relate pharmacokinetics to pharmacodynamics and efficacy by following the time above a threshold concentration. On the basis of its oral route of administration, a selectivity profile that favors Aurora-driven pharmacology and its activity against multidrug-resistant cell lines, 23r was identified as a potential best-in-class Aurora kinase inhibitor. In phase 1 dose expansion studies with G-CSF support, 23r has shown promising single agent activity.