Discovery of (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations

被引：461

作者：

Johnson, Ted W. ^{[1
]}

Richardson, Paul F. ^{[1
]}

Bailey, Simon ^{[1
]}

Brooun, Alexei ^{[1
]}

Burke, Benjamin J. ^{[1
]}

Collins, Michael R. ^{[1
]}

Cui, J. Jean ^{[1
]}

Deal, Judith G. ^{[1
]}

Deng, Ya-Li ^{[1
]}

Dinh, Dac ^{[1
]}

Engstrom, Lars D. ^{[1
]}

He, Mingying ^{[1
]}

Hoffman, Jacqui ^{[1
]}

Hoffman, Robert L. ^{[1
]}

Huang, Qinhua ^{[1
]}

Kania, Robert S. ^{[1
]}

Kath, John C. ^{[1
]}

Lam, Hieu ^{[1
]}

Lam, Justine L. ^{[1
]}

Le, Phuong T. ^{[1
]}

Lingardo, Laura ^{[1
]}

Liu, Wei ^{[1
]}

McTigue, Michele ^{[1
]}

Palmer, Cynthia L. ^{[1
]}

Sach, Neal W. ^{[1
]}

Smeal, Tod ^{[1
]}

Smith, Graham L. ^{[1
]}

Stewart, Albert E. ^{[1
]}

Timofeevski, Sergei ^{[1
]}

Zhu, Huichun ^{[1
]}

Zhu, Jinjiang ^{[1
]}

Zou, Helen Y. ^{[1
]}

Edwards, Martin P. ^{[1
]}

机构：

[1] Pfizer Worldwide Res & Dev, La Jolla Labs, San Diego, CA 92121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 11期

关键词：

P-GLYCOPROTEIN; LIPOPHILIC EFFICIENCY; ACTIVATING MUTATIONS; THERAPEUTIC TARGET; DIRECT ARYLATION; BLOOD-BRAIN; GENE; IDENTIFICATION; SYSTEM; FUSION;

D O I：

10.1021/jm500261q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocydic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocydic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.

引用

页码：4720 / 4744

页数：25

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