PMID- 24055079
OWN - NLM
STAT- MEDLINE
DCOM- 20140526
LR  - 20131007
IS  - 1464-3391 (Electronic)
IS  - 0968-0896 (Linking)
VI  - 21
IP  - 21
DP  - 2013 Nov 1
TI  - 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.
PG  - 6349-58
LID - S0968-0896(13)00749-9 [pii]
LID - 10.1016/j.bmc.2013.08.046 [doi]
AB  - 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 pi-cation interaction with Arg322, a pi-pi 
      stacking with Trp389, and a pi-pi 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.
CI  - Copyright (c) 2013 Elsevier Ltd. All rights reserved.
FAU - Deng, Guanghui
AU  - Deng G
AD  - Research and Development, GlaxoSmithKline Pharmaceuticals, 898 Halei Road, 
      Zhangjiang Hi-tech Park, Pudong, Shanghai 201203, China.
FAU - Zhao, Baowei
AU  - Zhao B
FAU - Ma, Yingli
AU  - Ma Y
FAU - Xu, Qiongfeng
AU  - Xu Q
FAU - Wang, Hailong
AU  - Wang H
FAU - Yang, Liuqing
AU  - Yang L
FAU - Zhang, Qing
AU  - Zhang Q
FAU - Guo, Taylor B
AU  - Guo TB
FAU - Zhang, Wei
AU  - Zhang W
FAU - Jiao, Yang
AU  - Jiao Y
FAU - Cai, Xin
AU  - Cai X
FAU - Zhang, Jinqiang
AU  - Zhang J
FAU - Liu, Houfu
AU  - Liu H
FAU - Guan, Xiaoming
AU  - Guan X
FAU - Lu, Hongtao
AU  - Lu H
FAU - Xiang, Jianing
AU  - Xiang J
FAU - Elliott, John D
AU  - Elliott JD
FAU - Lin, Xichen
AU  - Lin X
FAU - Ren, Feng
AU  - Ren F
LA  - eng
PT  - Journal Article
DEP - 20130903
PL  - England
TA  - Bioorg Med Chem
JT  - Bioorganic & medicinal chemistry
JID - 9413298
RN  - 0 (Aza Compounds)
RN  - 0 (Prolyl-Hydroxylase Inhibitors)
RN  - 0 (Pyridines)
RN  - 0 (Spiro Compounds)
RN  - EC 1.14.11.2 (EGLN1 protein, human)
RN  - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
SB  - IM
MH  - Administration, Oral
MH  - Animals
MH  - Aza Compounds/*chemistry
MH  - Binding Sites
MH  - Crystallography, X-Ray
MH  - Half-Life
MH  - Humans
MH  - Hypoxia-Inducible Factor-Proline Dioxygenases/*antagonists & 
      inhibitors/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Molecular Docking Simulation
MH  - Prolyl-Hydroxylase Inhibitors/chemical synthesis/*chemistry/pharmacokinetics
MH  - Protein Binding
MH  - Protein Structure, Tertiary
MH  - Pyridines/chemical synthesis/*chemistry/pharmacokinetics
MH  - Spiro Compounds/chemical synthesis/chemistry/pharmacokinetics
MH  - Structure-Activity Relationship
OTO - NOTNLM
OT  - 2,8-Diazaspiro[4.5]decan-1-one
OT  - Hypoxia inducible factor (HIF)
OT  - PHD inhibitors
OT  - PHD2 crystal structure
OT  - Prolyl hydroxylase domain-containing protein 2 (PHD2)
OT  - SAR study
EDAT- 2013/09/24 06:00
MHDA- 2014/05/27 06:00
CRDT- 2013/09/24 06:00
PHST- 2013/08/08 00:00 [received]
PHST- 2013/08/24 00:00 [revised]
PHST- 2013/08/24 00:00 [accepted]
PHST- 2013/09/24 06:00 [entrez]
PHST- 2013/09/24 06:00 [pubmed]
PHST- 2014/05/27 06:00 [medline]
AID - S0968-0896(13)00749-9 [pii]
AID - 10.1016/j.bmc.2013.08.046 [doi]
PST - ppublish
SO  - Bioorg Med Chem. 2013 Nov 1;21(21):6349-58. doi: 10.1016/j.bmc.2013.08.046. Epub 
      2013 Sep 3.