Structure-guided design of substituted aza-benzimidazoles as potent hypoxia inducible factor-1α prolyl hydroxylase-2 inhibitors

被引：26

作者：

Frohn, Mike ^{[1
]}

Viswanadhan, Vellarkad ^{[1
]}

Pickrell, Alexander J. ^{[1
]}

Golden, Jennifer E. ^{[1
]}

Muller, Kristine M. ^{[1
]}

Burli, Roland W. ^{[1
]}

Biddlecome, Gloria ^{[2
]}

Yoder, Sean C. ^{[2
]}

Rogers, Norma ^{[2
]}

Dao, Jennifer H. ^{[1
]}

Hungate, Randall ^{[1
]}

Allen, Jennifer R. ^{[1
]}

机构：

[1] Amgen Inc, Dept Chem Res & Discovery, Thousand Oaks, CA 91320 USA

[2] Amgen Inc, Dept Hematol, Thousand Oaks, CA 91320 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 18期

关键词：

PHD-2; HIF-1a; prolyl hydroxylase; hypoxia; normoxia; aza-benzimidazole;

D O I：

10.1016/j.bmcl.2008.08.012

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report the structure-based design and synthesis of a novel series of aza-benzimidazoles as PHD2 inhibitors. These efforts resulted in compound 22, which displayed highly potent inhibition of PHD2 function in vitro. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：5023 / 5026

页数：4

共 23 条

[1] Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor [J].

Appelhoff, RJ ;

Tian, YM ;

Raval, RR ;

Turley, H ;

Harris, AL ;

Pugh, CW ;

Ratcliffe, PJ ;

Gleadle, JM .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (37) :38458-38465

[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] Oxygen sensing in the hypoxic response pathway: regulation of the hypoxia-inducible transcription factor [J].

Bruick, RK .

GENES & DEVELOPMENT, 2003, 17 (21) :2614-2623

[4] FLAME: A program to flexibly align molecules [J].

Cho, SJ ;

Sun, YX .

JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2006, 46 (01) :298-306

[5] A 2ND GENERATION FORCE-FIELD FOR THE SIMULATION OF PROTEINS, NUCLEIC-ACIDS, AND ORGANIC-MOLECULES [J].

CORNELL, WD ;

CIEPLAK, P ;

BAYLY, CI ;

GOULD, IR ;

MERZ, KM ;

FERGUSON, DM ;

SPELLMEYER, DC ;

FOX, T ;

CALDWELL, JW ;

KOLLMAN, PA .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1995, 117 (19) :5179-5197

[6] Dioxygenases as O2-dependent regulators of the hypoxic response pathway [J].

Dann, CE ;

Bruick, RK .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2005, 338 (01) :639-647

[7] REGIOSELECTIVE CYANATION OF PYRIDINE 1-OXIDES WITH TRIMETHYLSILANECARBONITRILE - A MODIFIED REISSERT-HENZE REACTION [J].

FIFE, WK .

JOURNAL OF ORGANIC CHEMISTRY, 1983, 48 (08) :1375-1377

[8] New aryl/heteroaryl C-N bond cross-coupling reactions via arylboronic acid cupric acetate arylation [J].

Lam, PYS ;

Clark, CG ;

Saubern, S ;

Adams, J ;

Winters, MP ;

Chan, DMT ;

Combs, A .

TETRAHEDRON LETTERS, 1998, 39 (19) :2941-2944

[9] Improving docking accuracy through molecular mechanics generalized born optimization and scoring [J].

Lee, Matthew R. ;

Sun, Yaxiong .

JOURNAL OF CHEMICAL THEORY AND COMPUTATION, 2007, 3 (03) :1106-1119

[10] Cellular oxygen sensing:: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2) [J].

McDonough, Michael A. ;

Li, Vivian ;

Flashman, Emily ;

Chowdhury, Rasheduzzaman ;

Mohr, Christopher ;

Lienard, Benoit M. R. ;

Zondlo, James ;

Oldham, Neil J. ;

Clifton, Ian J. ;

Lewis, Jeffrey ;

McNeill, Luke A. ;

Kurzeja, Robert J. M. ;

Hewitson, Kirsty S. ;

Yang, Evelyn ;

Jordan, Steven ;

Syed, Rashid S. ;

Schofield, Christopher J. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (26) :9814-9819

← 1 2 3 →