Novel complex crystal structure of prolyl hydroxylase domain-containing protein 2 (PHD2): 2,8-Diazaspiro[4.5]decan-1-ones as potent, orally bioavailable PHD2 inhibitors
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- 作者：Guanghui Deng ; Baowei Zhao ; Yingli Ma ; Qiongfeng Xu ; Hailong Wang ; Liuqing Yang ; Qing Zhang ; Taylor B. Guo ; Wei Zhang ; Yang Jiao ; Xin Cai ; Jinqiang Zhang ; Houfu Liu ; Xiaoming Guan ; Hongtao Lu ; Jianing Xiang ; John D. Elliott ; Xichen Lin ; Feng Ren
- 关键词：2 ; 8-Diazaspiro[4.5]decan-1-one ; Prolyl hydroxylase domain-containing protein 2 (PHD2) ; PHD inhibitors ; Hypoxia inducible factor (HIF) ; PHD2 crystal structure ; SAR study
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2013
- 出版时间：1 November, 2013
- 年：2013
- 卷：21
- 期：21
- 页码：6349-6358
- 全文大小：3559 K
文摘
We have discovered a novel complex crystal structure of the PHD2 enzyme with its inhibitor, the 2,8-diazaspiro[4.5]decan-1-one analogue 4b. The widely reported salt bridge between Arg383 of the enzyme and its inhibitors in all complex structures published thus far was not observed in our case. In our complex structure compound 4b forms several novel interactions with the enzyme, which include a hydrogen bond with Arg322, a ¦Ð-cation interaction with Arg322, a ¦Ð-¦Ð stacking with Trp389, and a ¦Ð-¦Ð stacking with His313. Guided by the structural information, SAR studies were performed on the 2,8-diazaspiro[4.5]decan-1-one series leading to the discovery of compound 9p with high potency and good oral pharmacokinetic profile in mice.