Optimization of 2,3,5-trisubstituted pyridine derivatives as potent allosteric Akt1 and Akt2 inhibitors

被引：28

作者：

Hartnett, John C. ^{[1
]}

Barnett, Stanley F. ^{[2
]}

Bilodeau, Mark T. ^{[1
]}

Defeo-Jones, Deborah ^{[2
]}

Hartman, George D. ^{[1
]}

Huber, Hans E. ^{[2
]}

Jones, Raymond E. ^{[2
]}

Kral, Astrid M. ^{[2
]}

Robinson, Ronald G. ^{[2
]}

Wu, Zhicai ^{[1
]}

机构：

[1] Merck & Co Inc, Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck & Co Inc, Merck Res Labs, Dept Canc Res, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 06期

关键词：

inhibitors; Akt1; Akt2; enzymatic; cellular;

D O I：

10.1016/j.bmcl.2007.12.040

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

This letter shows inhibitor SAR on a pyridine series of allosteric Akt inhibitors to optimize enzymatic and cellular potency. We have optimized 2,3,5-trisubstituted pyridines to give potent Akt1 and Akt2 inhibitors in both enzyme and cell based assays. In addition, we will also highlight the pharmacokinetic pro. le of an optimized inhibitor that has low clearance and long half-life in dogs. (C) 2007 Elsevier Ltd. All rights reserved.

引用

页码：2194 / 2197

页数：4

共 20 条

[1] Identification and characterization of pleckstrin-homology-domain-dependent and isoenzyme-specific Akt inhibitors
Barnett, SF
Defeo-Jones, D
Fu, S
Hancock, PJ
Haskell, KM
Jones, RE
Kahana, JA
Kral, AM
Leander, K
Lee, LL
Malinowski, J
McAvoy, EM
Nahas, DD
Robinson, RG
Huber, HE
[J]. BIOCHEMICAL JOURNAL, 2005, 385 : 399 - 408
[2] Structure-based optimization of novel azepane derivatives as PKB inhibitors
Breitenlechner, CB
Wegge, T
Berillon, L
Graul, K
Marzenell, M
Friebe, WG
Thomas, U
Schumacher, R
Huber, R
Engh, RA
Masjost, B
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (06) : 1375 - 1390
[3] Brognard J, 2001, CANCER RES, V61, P3986
[4] Amplification of AKT2 in human pancreatic cancer cells and inhibition of ATK2 expression and tumorigenicity by antisense RNA
Cheng, JQ
Ruggeri, B
Klein, WM
Sonoda, G
Altomare, DA
Watson, DK
Testa, JR
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (08) : 3636 - 3641
[5] DeFeo-Jones D, 2005, MOL CANCER THER, V4, P271
[6] Graff Jeremy R, 2002, Expert Opin Ther Targets, V6, P103, DOI 10.1517/14728222.6.1.103
[7] Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC
Haas-Kogan, D
Shalev, N
Wong, M
Mills, G
Yount, G
Stokoe, D
[J]. CURRENT BIOLOGY, 1998, 8 (21) : 1195 - 1198
[8] PROTEIN KINASES .6. THE EUKARYOTIC PROTEIN-KINASE SUPERFAMILY - KINASE (CATALYTIC) DOMAIN-STRUCTURE AND CLASSIFICATION
HANKS, SK
HUNTER, T
[J]. FASEB JOURNAL, 1995, 9 (08) : 576 - 596
[9] Role of the AKT kinase in expansion of multiple myeloma clones: effects on cytokine-dependent proliferative and survival responses
Hsu, JH
Shi, YJ
Hu, LP
Fisher, M
Franke, TF
Lichtenstein, A
[J]. ONCOGENE, 2002, 21 (09) : 1391 - 1400
[10] TAK-599, a novel N-phosphono type prodrug of Anti-MRSA cephalosporin T-91825:: Synthesis, physicochemical and pharmacological properties
Ishikawa, T
Matsunaga, N
Tawada, H
Kuroda, N
Nakayama, Y
Ishibashi, Y
Tomimoto, M
Ikeda, Y
Tagawa, Y
Iizawa, Y
Okonogi, K
Hashiguchi, S
Miyake, A
[J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2003, 11 (11) : 2427 - 2437

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