Selection, synthesis, and structure–activity relationship of tetrahydropyrido[4,3-d]pyrimidine-2,4-diones as human GnRH receptor antagonists
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- 作者：Marion C. Lanier ; Miklos Feher ; Neil J. Ashweek ; Colin J. Loweth ; Jaimie K. Rueter ; Deborah H. Slee ; John P. Williams ; Yun-Fei Zhu ; Susan K. Sullivan ; Michael S. Brown
- 关键词：Gonadotropin ; GnRH ; LHRH ; Small molecule antagonist ; Tetrahydropyrido[4 ; 3-d]pyrimidine-2 ; 4-dione
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2007
- 出版时间：15 August 2007
- 年：2007
- 卷：15
- 期：16
- 页码：5590-5603
- 全文大小：314 K
文摘
The present article describes a selection of a new class of small molecule antagonists for the h-GnRH receptor, their preparation, and evaluation in vitro. Three computational methods were combined into a consensus score, to rank order virtual templates. The top 5 % of templates were further evaluated in silico and assessed for novelty and synthetic accessibility. The tetrahydropyrido[4,3-d]pyrimidine-2,4-dione core was selected for synthesis and evaluated in vitro. Using an array approach for analog design and synthesis, we were able to drive the binding below 10 nM for the h-GnRH receptor after two rounds of optimization.