Discovery and synthesis of novel 4-aminopyrrolopyrimidine Tie-2 kinase inhibitors for the treatment of solid tumors
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- 作者：Joel T. Arcari ; Jean S. Beebe ; Martin A. Berliner ; Vincent Bernardo ; Merin Boehm ; Gary V. Borzillo ; Tracey Clark ; Bruce D. Cohen ; Richard D. Connell ; Heather N. Frost ; Deborah A. Gordon ; William M. Hungerford ; Shefali M. Kakar ; Aaron Kanter ; Nandell F. Keene ; Elizabeth A. Knauth ; Susan D. LaGreca ; Yong Lu ; Louis Martinez-Alsina ; Matthew A. Marx ; Joel Morris ; Nandini C. Patel ; nandini.c.patel@pfizer.com ; Doug Savage ; Cathy I. Soderstrom ; Carl Thompson ; George Tkalcevic ; Norma J. Tom ; Felix F. Vajdos ; James J. Valentine ; Patrick W. Vincent ; Matthew D. Wessel ; Jinshan M. Chen ; michael.j.chen@pfizer.com
- 关键词：Tie-2 ; Kinase inhibitor ; Pyrrolopyrimidine ; Angiogenesis ; Cancer
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：15 May, 2013
- 年：2013
- 卷：23
- 期：10
- 页码：3059-3063
- 全文大小：1523 K
文摘
The synthesis and biological evaluation of novel Tie-2 kinase inhibitors are presented. Based on the pyrrolopyrimidine chemotype, several new series are described, including the benzimidazole series by linking a benzimidazole to the C5-position of the 4-amino-pyrrolopyrimidine core and the ketophenyl series synthesized by incorporating a ketophenyl group to the C5-position. Medicinal chemistry efforts led to potent Tie-2 inhibitors. Compound 15, a ketophenyl pyrrolopyrimidine urea analog with improved physicochemical properties, demonstrated favorable in vitro attributes as well as dose responsive and robust oral tumor growth inhibition in animal models.