Synthesis, structural analysis, and SAR studies of triazine derivatives as potent, selective Tie-2 inhibitors

被引：30

作者：

Hodous, Brian L.

Geuns-Meyer, Stephanie D.

Hughes, Paul E.

Albrecht, Brian K.

Bellon, Steve

Caenepeel, Sean

Cee, Victor J.

Chaffee, Stuart C.

Emery, Maurice

Fretland, Jenne

Gallant, Paul

Gu, Yan

Johnson, Rebecca E.

Kim, Joseph L.

Long, Alexander M.

Morrison, Michael

Olivieri, Philip R.

Patel, Vinod F.

Polverino, Anthony

Rose, Paul

Wang, Ling

Zhao, Huilin

机构：

[1] Amgen Inc, Dept Med Chem, Cambridge, MA 02139 USA

[2] Amgen Inc, Dept Mol Pharmacol, Cambridge, MA 02139 USA

[3] Amgen Inc, Dept Mol Struct, Cambridge, MA 02139 USA

[4] Amgen Inc, Dept Oncol Res, Thousand Oaks, CA 91320 USA

[5] Amgen Inc, Dept Pharmacokinet & Drug Metab, Thousand Oaks, CA 91320 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 10期

关键词：

Tie-2; kinase; oncology; small molecule kinase inhibitors; triazine; KDR;

D O I：

10.1016/j.bmcl.2007.02.067

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel class of selective Tie-2 inhibitors was derived from a multi-kinase inhibitor 1. By reversing the amide connectivity and incorporating aminotriazine or aminopyridine hinge-binding moieties, excellent Tie-2 potency and KDR selectivity could be achieved with 3-substituted terminal aryl rings. X-ray co-crystal structure analysis aided inhibitor design. This series was evaluated on the basis of potency, selectivity, and rat pharmacokinetic parameters. (c) 2007 Elsevier Ltd. All rights reserved.

引用

收藏

页码：2886 / 2889

页数：4

相关论文

共 14 条

[1] COMP-Ang1: A designed angiopoietin-1 variant with nonleaky angiogenic activity [J].

Cho, CH ;

Kammerer, RA ;

Lee, HJ ;

Steinmetz, MO ;

Ryu, YS ;

Lee, SH ;

Yasunaga, K ;

Kim, KT ;

Kim, I ;

Choi, HH ;

Kim, W ;

Kim, SH ;

Park, SK ;

Lee, GM ;

Koh, GY .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (15) :5547-5552

[2] WHAT IS THE EVIDENCE THAT TUMORS ARE ANGIOGENESIS DEPENDENT [J].

FOLKMAN, J .

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1990, 82 (01) :4-6

[3] ANTI-ANGIOGENESIS - NEW CONCEPT FOR THERAPY OF SOLID TUMORS [J].

FOLKMAN, J .

ANNALS OF SURGERY, 1972, 175 (03) :409-&

[4] Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine tie-2 kinase inhibitor [J].

Hodous, Brian L. ;

Geuns-Meyer, Stephanie D. ;

Hughes, Paul E. ;

Albrecht, Brian K. ;

Bellon, Steve ;

Bready, James ;

Caenepeel, Sean ;

Cee, Victor J. ;

Chaffee, Stuart C. ;

Coxon, Angela ;

Emery, Maurice ;

Fretland, Jenne ;

Gallant, Paul ;

Gu, Yan ;

Hoffman, Doug ;

Johnson, Rebecca E. ;

Kendall, Richard ;

Kim, Joseph L. ;

Long, Alexander M. ;

Morrison, Michael ;

Olivieri, Philip R. ;

Patel, Vinod F. ;

Polverino, Anthony ;

Rose, Paul ;

Tempest, Paul ;

Wang, Ling ;

Whittington, Douglas A. ;

Zhao, Huilin .

JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (04) :611-626

[5] DORMANCY OF MICROMETASTASES - BALANCED PROLIFERATION AND APOPTOSIS IN THE PRESENCE OF ANGIOGENESIS SUPPRESSION [J].

HOLMGREN, L ;

OREILLY, MS ;

FOLKMAN, J .

NATURE MEDICINE, 1995, 1 (02) :149-153

[6] Discovery and characterization of triaminotriazine aniline amides as highly selective p38 kinase inhibitors [J].

Lin, Tsung H. ;

Metzger, Axel ;

Diller, David J. ;

Desai, Madhuri ;

Henderson, Ian ;

Ahmed, Gulzar ;

Kimble, Earl F. ;

Quadros, Elizabeth ;

Webb, Maria L. .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2006, 318 (02) :495-502

[7] Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo [J].

Lobov, IB ;

Brooks, PC ;

Lang, RA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (17) :11205-11210

[8] Bevacizumab in the treatment of colorectal cancer [J].

Mulcahy, MF ;

Benson, A .

EXPERT OPINION ON BIOLOGICAL THERAPY, 2005, 5 (07) :997-1005

[9] Mechanisms of angiogenesis [J].

Risau, W .

NATURE, 1997, 386 (6626) :671-674

[10] The Tie-2 ligand Angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism [J].

Scharpfenecker, M ;

Fiedler, U ;

Reiss, Y ;

Augustin, HG .

JOURNAL OF CELL SCIENCE, 2005, 118 (04) :771-780