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Comprehensive analysis of kinase inhibitor selectivity.激酶抑制剂选择性的综合分析。
Nat Biotechnol. 2011 Oct 30;29(11):1046-51. doi: 10.1038/nbt.1990.
3
Metabolism of 4-Aminopiperidine Drugs by Cytochrome P450s: Molecular and Quantum Mechanical Insights into Drug Design.细胞色素P450对4-氨基哌啶类药物的代谢：药物设计的分子与量子力学见解
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Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.小分子激酶抑制剂的激活状态依赖性结合：来自生物化学的结构见解
Chem Biol. 2010 Nov 24;17(11):1241-9. doi: 10.1016/j.chembiol.2010.09.010.
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Blood. 2010 Feb 18;115(7):1461-71. doi: 10.1182/blood-2009-08-237412. Epub 2009 Dec 11.
6
JNJ-28312141, a novel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia.JNJ-28312141，一种新型的口服活性集落刺激因子-1 受体/FMS 相关酪氨酸激酶受体酪氨酸激酶抑制剂，具有治疗实体瘤、骨转移和急性髓系白血病的潜力。
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AC710的发现，一种血小板衍生生长因子受体家族激酶的全球选择性抑制剂。

Discovery of AC710, a Globally Selective Inhibitor of Platelet-Derived Growth Factor Receptor-Family Kinases.

作者信息

Liu Gang, Campbell Brian T, Holladay Mark W, Ford Pulido Julia M, Hua Helen, Gitnick Dana, Gardner Michael F, James Joyce, Breider Mike A, Brigham Daniel, Belli Barbara, Armstrong Robert C, Treiber Daniel K

机构信息

Departments of Medicinal Chemistry, Cell Biology and Pharmacology, Technology Development, and DMPK and Toxicology, 4215 Sorrento Valley Boulevard, San Diego, California 92121, United States.

出版信息

ACS Med Chem Lett. 2012 Sep 24;3(12):997-1002. doi: 10.1021/ml300214g. eCollection 2012 Dec 13.

DOI:10.1021/ml300214g
PMID:24900421
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4025831/
Abstract

A series of potent, selective platelet-derived growth factor receptor-family kinase inhibitors was optimized starting from a globally selective lead molecule 4 through structural modifications aimed at improving the physiochemical and pharmacokinetic properties, as exemplified by 18b. Further clearance reduction via per-methylation of the α-carbons of a solubilizing piperidine nitrogen resulted in advanced leads 22a and 22b. Results from a mouse tumor xenograft, a collagen-induced arthritis model, and a 7 day rat in vivo tolerability study culminated in the selection of compound 22b (AC710) as a preclinical development candidate.

摘要

从具有全球选择性的先导分子4开始，通过旨在改善物理化学和药代动力学性质的结构修饰，优化了一系列强效、选择性血小板衍生生长因子受体家族激酶抑制剂，如18b所示。通过对增溶哌啶氮的α-碳进行全甲基化进一步降低清除率，得到了先进的先导化合物22a和22b。小鼠肿瘤异种移植、胶原诱导的关节炎模型和为期7天的大鼠体内耐受性研究的结果最终选定化合物22b（AC710）作为临床前开发候选药物。