Synthesis and Evaluation of a New Generation of Orally Efficacious Benzimidazole-Based Poly(ADP-ribose) Polymerase-1 (PARP-1) Inhibitors as Anticancer Agents

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• 作者：Yunsong Tong ; Jennifer J. Bouska ; Paul A. Ellis ; Eric F. Johnson ; Joel Leverson ; Xuesong Liu ; Patrick A. Marcotte ; Amanda M. Olson ; Donald J. Osterling ; Magdalena Przytulinska ; Luis E. Rodriguez ; Yan
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：November 12, 2009
• 年：2009
• 卷：52
• 期：21
• 页码：6803-6813
• 全文大小：1069K
• 年卷期：v.52,no.21(November 12, 2009)
• ISSN：1520-4804

文摘

Small molecule inhibitors of PARP-1 have been pursued by various organizations as potential therapeutic agents either capable of sensitizing cytotoxic treatments or acting as stand-alone agents to combat cancer. As one of the strategies to expand our portfolio of PARP-1 inhibitors, we pursued unsaturated heterocycles to replace the saturated cyclic amine derivatives appended to the benzimidazole core. Not only did a variety of these new generation compounds maintain high enzymatic potency, many of them also displayed robust cellular activity. For example, the enzymatic IC₅₀ and cellular EC₅₀ values were as low as 1 nM or below. Compounds 24 (EC₅₀ = 3.7 nM) and 44 (EC₅₀ = 7.8 nM), featuring an oxadiazole and a pyridine moiety, respectively, demonstrated balanced potency and PK profiles. In addition, these two molecules exhibited potent oral in vivo efficacy in potentiating the cytotoxic agent temozolomide in a B16F10 murine melanoma model.