Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach,Journal of Medicinal Chemistry

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Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-11-20 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00883
Upendra Rao Anumala ₁ , Jo Waaler _{2,

3} , Yves Nkizinkiko ₄ , Alexander Ignatev ₄ , Katina Lazarow ₁ , Peter Lindemann ₁ , Petter Angell Olsen _{2,

3} , Sudarshan Murthy ₄ , Ezeogo Obaji ₄ , Alexander G. Majouga ₅ , Sergey Leonov _{6,

7} , Jens Peter von Kries _{1,

8} , Lari Lehtiö ₄ , Stefan Krauss _{2,

3} , Marc Nazaré _{1,

8}

Affiliation

A structure-guided hybridization approach using two privileged substructures gave instant access to a new series of tankyrase inhibitors. The identified inhibitor 16 displays high target affinity on tankyrase 1 and 2 with biochemical and cellular IC₅₀ values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity toward other poly (ADP-ribose) polymerase enzymes. The identified inhibitor shows a favorable in vitro ADME profile as well as good oral bioavailability in mice, rats, and dogs. Critical for the approach was the utilization of an appropriate linker between 1,2,4-triazole and benzimidazolone moieties, whereby a cyclobutyl linker displayed superior affinity compared to a cyclohexane and phenyl linker.

中文翻译：

通过杂交方法发现一系列新颖的坦科聚合酶抑制剂

使用两个特权子结构的结构指导杂交方法可立即获得一系列新的tankyrase抑制剂。鉴定出的抑制剂16对tankyrase 1和2表现出较高的靶亲和力，其生化和细胞IC ₅₀值分别为29 nM，6.3 nM和19 nM，并且对其他聚ADP-核糖聚合酶的选择性高。鉴定出的抑制剂在小鼠，大鼠和狗中显示出良好的体外ADME活性以及良好的口服生物利用度。该方法的关键是在1,2,4-三唑和苯并咪唑酮部分之间使用适当的连接基，与环己烷和苯基连接基相比，环丁基连接基显示出优异的亲和力。

更新日期：2017-11-20

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