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 with Activity against Multidrug-Resistant Cancer Cell Lines
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 with Activity against Multidrug-Resistant Cancer Cell Lines
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DOI：
10.1021/acs.jmedchem.5b00183
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发表时间：
2015-07-09
影响因子：
7.3
通讯作者：
Payton, Marc
中科院分区：
文献类型：
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作者：
Geuns-Meyer, Stephanie;Cee, Victor J.;Payton, Marc
改善极光激酶抑制剂14a的物理性质和代谢稳定性的努力表明，极性增加会降低其对多药耐药细胞系的效力。尽管23r （AMG 900）具有较高的体外代谢内在清除率，但其表现出可接受的药代动力学特性和强大的药效学活性。由于酶和细胞数据之间的脱节，结合动力学指标复杂且明显矛盾，以及血浆中不可测量的游离分数，从体外数据到体内目标覆盖范围的预测是不切实际的。相比之下，通过跟踪超过阈值浓度的时间，可以直接将药代动力学与药效学和疗效联系起来。基于其口服给药途径、有利于极光驱动药理学的选择性特征及其对多药耐药细胞系的活性，23r被确定为潜在的同类最佳极光激酶抑制剂。在G-CSF支持的1期剂量扩展研究中，23r显示出有希望的单药活性。
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.