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.
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 π-cation interaction with Arg322, a π-π stacking with Trp389, and a π-π 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.
Research and Development, GlaxoSmithKline Pharmaceuticals, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201203, China.
Guanghui
G
Deng
Baowei
B
Zhao
Yingli
Y
Ma
Qiongfeng
Q
Xu
Hailong
H
Wang
Liuqing
L
Yang
Qing
Q
Zhang
Taylor B
TB
Guo
Wei
W
Zhang
Yang
Y
Jiao
Xin
X
Cai
Jinqiang
J
Zhang
Houfu
H
Liu
Xiaoming
X
Guan
Hongtao
H
Lu
Jianing
J
Xiang
John D
JD
Elliott
Xichen
X
Lin
Feng
F
Ren
D000284:Administration, Oral; D000818:Animals; D001372:Aza Compounds / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006207:Half-Life; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D064800:Prolyl-Hydroxylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
D001372:Aza Compounds; D064800:Prolyl-Hydroxylase Inhibitors; D011725:Pyridines; D013141:Spiro Compounds; C490190:EGLN1 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
2,8-Diazaspiro[4.5]decan-1-one; Hypoxia inducible factor (HIF); PHD inhibitors; PHD2 crystal structure; Prolyl hydroxylase domain-containing protein 2 (PHD2); SAR study