Structure鈥揈fficiency Relationship of [1,2,4]Triazol-3-ylamines as Novel Nicotinamide Isosteres that Inhibit Tankyrases

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• 作者：Michael D. Shultz ; Dyuti Majumdar ; Donovan N. Chin ; Pascal D. Fortin ; Yun Feng ; Ty Gould ; Christina A. Kirby ; Travis Stams ; Nigel J. Waters ; Wenlin Shao
• 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：7049-7059
• 全文大小：454K
• 年卷期：v.56,no.17(September 12, 2013)
• ISSN：1520-4804

文摘

Tankyrases 1 and 2 are members of the poly(ADP-ribose) polymerase (PARP) family of enzymes that modulate Wnt pathway signaling. While amide- and lactam-based nicotinamide mimetics that inhibit tankyrase activity, such as XAV939, are well-known, herein we report the discovery and evaluation of a novel nicotinamide isostere that demonstrates selectivity over other PARP family members. We demonstrate the utilization of lipophilic efficiency-based structure鈥揺fficiency relationships (SER) to rapidly drive the evaluation of this series. These efforts led to a series of selective, cell-active compounds with solubility, physicochemical, and in vitro properties suitable for further optimization.