4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: Potent and selective p70S6 kinase inhibitors

被引：30

作者：

Bandarage, Upul ^{[1
]}

Hare, Brian ^{[1
]}

Parsons, Jonathan ^{[1
]}

Pham, Ly ^{[1
]}

Marhefka, Craig ^{[1
]}

Bemis, Guy ^{[1
]}

Tang, Qing ^{[1
]}

Moody, Cameron Stuver ^{[1
]}

Rodems, Steve ^{[2
]}

Shah, Sundeep ^{[2
]}

Adams, Chris ^{[3
]}

Bravo, Jose ^{[3
]}

Charonnet, Emmanuelle ^{[3
]}

Savic, Vladimir ^{[3
]}

Come, Jon H. ^{[1
]}

Green, Jeremy ^{[1
]}

机构：

[1] Vertex Pharmaceut Inc, Cambridge, MA 02139 USA

[2] Vertex Pharmaceut Inc, San Diego, CA 92121 USA

[3] Biofocus, Saffron Walden CB10 1XL, Essex, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 17期

关键词：

p70S6K; p70S6; Kinase; 1,2,5-Oxadiazole; 3-Aminofurazan; RHO-KINASE; MSK-1-INHIBITORS;

D O I：

10.1016/j.bmcl.2009.07.022

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

We report herein the design and synthesis of 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-amine derivatives as inhibitors of p70S6 kinase. Screening hits containing the 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine scaffold were optimized for p70S6K potency and selectivity against related kinases. Structure-based design employing an active site homology model derived from PKA led to the preparation of benzimidazole 5-substituted compounds 26 and 27 as highly potent inhibitors (K-i < 1 nM) of p70S6K, with > 100-fold selectivity against PKA, ROCK and GSK3. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：5191 / 5194

页数：4

共 12 条

[1]

Andrianov V G., 1994, Chem. Heterocycl. Compd, V30, P608, DOI [10.1007/BF01169844, DOI 10.1007/BF01169844]

[2]

(1H-Imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives:: A novel class of potent MSK-1-inhibitors [J].

Bamford, MJ ;

Alberti, MJ ;

Bailey, N ;

Davies, S ;

Dean, DK ;

Gaiba, A ;

Garland, S ;

Harling, JD ;

Jung, DK ;

Panchal, TA ;

Parr, CA ;

Steadman, JG ;

Takle, AK ;

Townsend, JT ;

Wilson, DM ;

Witherington, J .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (14) :3402-3406

[3]

(1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives:: Further optimisation as highly potent and selective MSK-1-inhibitors [J].

Bamford, MJ ;

Bailey, N ;

Davies, S ;

Dean, DK ;

Francis, L ;

Panchal, TA ;

Parr, CA ;

Sehmi, S ;

Steadman, JG ;

Takle, AK ;

Townsend, JT ;

Wilson, DM .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (14) :3407-3411

[4]

Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities [J].

Doe, Chris ;

Bentley, Ross ;

Behm, David J. ;

Lafferty, Robert ;

Stavenger, Robert ;

Jung, David ;

Bamford, Mark ;

Panchal, Terry ;

Grygielko, Eugene ;

Wright, Lois L. ;

Smith, Gary K. ;

Chen, Zunxuan ;

Webb, Christine ;

Khandekar, Sanjay ;

Yi, Tracey ;

Kirkpatrick, Robert ;

Dul, Edward ;

Jolivette, Larry ;

Marino, Joseph P. ;

Willette, Robert ;

Lee, Dennis ;

Hu, Erding .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2007, 320 (01) :89-98

[5]

Genomic analysis of the eukaryotic protein kinase superfamily: a perspective [J].

Hanks, SK .

GENOME BIOLOGY, 2003, 4 (05)

[6]

Restraining PI3K: mTOR signalling goes back to the membrane [J].

Harrington, LS ;

Findlay, GM ;

Lamb, RF .

TRENDS IN BIOCHEMICAL SCIENCES, 2005, 30 (01) :35-42

[7]

Nobukini Takahiro, 2004, Novartis Found Symp, V262, P148

[8]

Synthesis and in vitro characterization of 1-(4-aminofurazan-3-yl)-5-dialkylaminomethyl-1H-[1,2,3]triazole-4-carboxylic acid derivatives.: A new class of selective GSK-3 inhibitors [J].

Olesen, PH ;

Sorensen, AR ;

Urso, B ;

Kurtzhals, P ;

Bowler, AN ;

Ehrbar, U ;

Hansen, BF .

JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (15) :3333-3341

[9]

Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signaling [J].

Radimerski, T ;

Montagne, J ;

Hemmings-Mieszczak, M ;

Thomas, G .

GENES & DEVELOPMENT, 2002, 16 (20) :2627-2632

[10]

Discovery of aminofurazan-azabenzimidazoles as inhibitors of Rho-kinase with high kinase selectivity and antihypertensive activity [J].

Stavenger, Robert A. ;

Cui, Haifeng ;

Dowdell, Sarah E. ;

Franz, Robert G. ;

Gaitanopoulos, Dimitri E. ;

Goodman, Krista B. ;

Hilfiker, Mark A. ;

Ivy, Robert L. ;

Leber, Jack D. ;

Marino, Joseph P., Jr. ;

Oh, Hye-Ja ;

Viet, Andrew Q. ;

Xu, Weiwei ;

Ye, Guosen ;

Zhang, Daohua ;

Zhao, Yongdong ;

Jolivette, Larry J. ;

Head, Martha S. ;

Semus, Simon F. ;

Elkins, Patricia A. ;

Kirkpatrick, Robert B. ;

Dul, Edward ;

Khandekar, Sanjay S. ;

Yi, Tracey ;

Jung, David K. ;

Wright, Lois L. ;

Smith, Gary K. ;

Behm, David J. ;

Doe, Christopher P. ;

Bentley, Ross ;

Chen, Zunxuan X. ;

Hu, Erding ;

Lee, Dennis .

JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (01) :2-5

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