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

被引：16

作者：

Deng, Guanghui ^{[1
]}

Zhao, Baowei ^{[1
]}

Ma, Yingli ^{[1
]}

Xu, Qiongfeng ^{[1
]}

Wang, Hailong ^{[1
]}

Yang, Liuqing ^{[1
]}

Zhang, Qing ^{[1
]}

Guo, Taylor B. ^{[1
]}

Zhang, Wei ^{[1
]}

Jiao, Yang ^{[1
]}

Cai, Xin ^{[1
]}

Zhang, Jinqiang ^{[1
]}

Liu, Houfu ^{[1
]}

Guan, Xiaoming ^{[1
]}

Lu, Hongtao ^{[1
]}

Xiang, Jianing ^{[1
]}

Elliott, John D. ^{[1
]}

Lin, Xichen ^{[1
]}

Ren, Feng ^{[1
]}

机构：

[1] GlaxoSmithKline, Res & Dev, Shanghai 201203, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2013年 / 21卷 / 21期

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; HYPOXIA-INDUCIBLE FACTOR; OXYGEN; HIF; ANEMIA; CHEMISTRY; BINDING;

D O I：

10.1016/j.bmc.2013.08.046

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：6349 / 6358

页数：10

共 28 条

[1] Nuclear Oxygen Sensing: Induction of Endogenous Prolyl-hydroxylase 2 Activity by Hypoxia and Nitric Oxide [J].

Berchner-Pfannschmidt, Utta ;

Tug, Suzan ;

Trinidad, Buena ;

Oehme, Felix ;

Yamac, Hatice ;

Wotzlaw, Christoph ;

Flamme, Ingo ;

Fandrey, Joachim .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (46) :31745-31753

[2] HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1α in normoxia [J].

Berra, E ;

Benizri, E ;

Ginouvès, A ;

Volmat, V ;

Roux, D ;

Pouysségur, J .

EMBO JOURNAL, 2003, 22 (16) :4082-4090

[3] Prolyl hydroxylases as regulators of cell metabolism [J].

Boulahbel, Houda ;

Duran, Raul V. ;

Gottlieb, Eyal .

BIOCHEMICAL SOCIETY TRANSACTIONS, 2009, 37 :291-294

[4] A conserved family of prolyl-4-hydroxylases that modify HIF [J].

Bruick, RK ;

McKnight, SL .

SCIENCE, 2001, 294 (5545) :1337-1340

[5] Structural Basis for Binding of Hypoxia-Inducible Factor to the Oxygen-Sensing Prolyl Hydroxylases [J].

Chowdhury, Rasheduzzaman ;

McDonough, Michael A. ;

Mecinovic, Jasmin ;

Loenarz, Christoph ;

Flashman, Emily ;

Hewitson, Kirsty S. ;

Domene, Carmen ;

Schofield, Christopher J. .

STRUCTURE, 2009, 17 (07) :981-989

[6] Dynamic Combinatorial Chemistry Employing Boronic Acids/Boronate Esters Leads to Potent Oxygenase Inhibitors [J].

Demetriades, Marina ;

Leung, Ivanhoe K. H. ;

Chowdhury, Rasheduzzaman ;

Chan, Mun Chiang ;

McDonough, Michael A. ;

Yeoh, Kar Kheng ;

Tian, Ya-Min ;

Claridge, Timothy D. W. ;

Ratcliffe, Peter J. ;

Woon, Esther C. Y. ;

Schofield, Christopher J. .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2012, 51 (27) :6672-6675

[7] Coot:: model-building tools for molecular graphics [J].

Emsley, P ;

Cowtan, K .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2004, 60 :2126-2132

[8]

EVDOKIMOV AG, 2008, Patent No. 20080124740

[9]

FLETCHER JM, 2008, Patent No. 2008144266

[10] Role and regulation of prolyl hydroxylase domain proteins [J].

Fong, G-H ;

Takeda, K. .

CELL DEATH AND DIFFERENTIATION, 2008, 15 (04) :635-641

← 1 2 3 →