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Bioorg Med Chem. 2013 Nov 1;21(21):6349-58. doi: 10.1016/j.bmc.2013.08.046. Epub 2013 Sep 3.

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.

Author information

1
Research and Development, GlaxoSmithKline Pharmaceuticals, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201203, China.

Abstract

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.

KEYWORDS:

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

PMID:
24055079
DOI:
10.1016/j.bmc.2013.08.046
[Indexed for MEDLINE]

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