Lessons from (S)-6-(1-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (PF-04254644), an Inhibitor of Receptor Tyrosine Kinase c-Met with High Pr

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• 作者：J. Jean Cui ; Hong Shen ; Michelle Tran-Dub茅 ; Mitchell Nambu ; Michele McTigue ; Neil Grodsky ; Kevin Ryan ; Shinji Yamazaki ; Shirley Aguirre ; Max Parker ; Qiuhua Li ; Helen Zou ; James Christensen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September 12, 2013
• 年：2013
• 卷：56
• 期：17
• 页码：6651-6665
• 全文大小：724K
• 年卷期：v.56,no.17(September 12, 2013)
• ISSN：1520-4804

文摘

The hepatocyte growth factor (HGF)/c-Met signaling axis is deregulated in many cancers and plays important roles in tumor invasive growth and metastasis. An exclusively selective c-Met inhibitor (S)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (8) was discovered from a highly selective high-throughput screening hit via structure-based drug design and medicinal chemistry lead optimization. Compound 8 had many attractive properties meriting preclinical evaluation. Broad off-target screens identified 8 as a pan-phosphodiesterase (PDE) family inhibitor, which was implicated in a sustained increase in heart rate, increased cardiac output, and decreased contractility indices, as well as myocardial degeneration in in vivo safety evaluations in rats. Compound 8 was terminated as a preclinical candidate because of a narrow therapeutic window in cardio-related safety. The learning from multiparameter lead optimization and strategies to avoid the toxicity attrition at the late stage of drug discovery are discussed.