5-(1,3-Benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives as potent and selective transforming growth factor-β type I receptor inhibitors

被引：18

作者：

Amada, Hideaki ^{[1
]}

Sekiguchi, Yoshinori ^{[1
]}

Ono, Naoya ^{[1
]}

Koami, Takeshi ^{[1
]}

Takayama, Tetsuo ^{[1
]}

Yabuuchi, Tetsuya ^{[1
]}

Katakai, Hironori ^{[1
]}

Ikeda, Akiko ^{[2
]}

Aoki, Mari ^{[2
]}

Naruse, Takumi ^{[2
]}

Wada, Reiko ^{[2
]}

Nozoe, Akiko ^{[3
]}

Sato, Masakazu ^{[1
]}

机构：

[1] Taisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, Japan

[2] Taisho Pharmaceut Co Ltd, Mol Funct & Pharmacol Labs, Kita Ku, Saitama 3319530, Japan

[3] Taisho Pharmaceut Co Ltd, Pharmaceut Technol Labs, Kita Ku, Saitama 3319530, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2012年 / 20卷 / 24期

关键词：

ALK5; inhibitor; Transforming growth factor-beta; Solubility; Topical application; Alopecia; TGF-BETA; HAIR-FOLLICLES; CELL-MEMBRANE; IDENTIFICATION; DESIGN; ALK5;

D O I：

10.1016/j.bmc.2012.09.066

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：

A series of 5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives was synthesized as transforming growth factor-beta (TGF-beta) type I receptor (also known as activin-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and for their TGF-beta-induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. As a representative compound, 16i was a potent and selective ALK5 inhibitor, exhibiting a good enzyme inhibitory activity (IC50 = 5.5 nM) as well as inhibitory activity against TGF-beta-induced Smad2/3 phosphorylation at a cellular level (IC50 = 36 nM). Furthermore, the topical application of 3% 16i lotion significantly inhibited Smad2 phosphorylation in Mouse skin (90% inhibition compared with vehicle-treated animals). (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：7128 / 7138

页数：11

共 23 条

[1]

Agrotis Alex, 2005, Current Vascular Pharmacology, V3, P55, DOI 10.2174/1570161052773951

[2] Design, synthesis, and evaluation of novel 4-thiazolylimidazoles as inhibitors of transforming growth factor-β type I receptor kinase [J].

Amada, Hideaki ;

Sekiguchi, Yoshinori ;

Ono, Naoya ;

Matsunaga, Yuko ;

Koami, Takeshi ;

Asanuma, Hajime ;

Shiozawa, Fumiyasu ;

Endo, Mayumi ;

Ikeda, Akiko ;

Aoki, Mari ;

Fujimoto, Natsuko ;

Wada, Reiko ;

Sato, Masakazu .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (05) :2024-2029

[3] OXONIUM ION ELECTROPHILES - SYNTHESIS OF THE HYPOTENSIVE OUDENONE [J].

BATES, HA ;

FARINA, J .

JOURNAL OF ORGANIC CHEMISTRY, 1985, 50 (20) :3843-3845

[4] TGFβ:: the molecular Jekyll and Hyde of cancer [J].

Bierie, Brian ;

Moses, Harold L. .

NATURE REVIEWS CANCER, 2006, 6 (07) :506-520

[5] Identification of novel inhibitors of the transforming growth factor β1 (TGF-β1) type 1 receptor (ALK5) [J].

Callahan, JF ;

Burgess, JL ;

Fornwald, JA ;

Gaster, LM ;

Harling, JD ;

Harrington, FP ;

Heer, J ;

Kwon, C ;

Lehr, R ;

Mathur, A ;

Olson, BA ;

Weinstock, J ;

Laping, NJ .

JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (05) :999-1001

[6] Control of murine hair follicle regression (catagen) by TGF-β1 in vivo [J].

Foitzik, K ;

Lindner, G ;

Mueller-Roever, S ;

Maurer, M ;

Botchkareva, N ;

Botchkarev, V ;

Handjiski, B ;

Metz, M ;

Hibino, T ;

Soma, T ;

Dotto, GP ;

Paus, R .

FASEB JOURNAL, 2000, 14 (05) :752-760

[7] Design of novel quinazoline derivatives and related analogues as potent and selective ALK5 inhibitors [J].

Gellibert, F. ;

Fouchet, M. -H. ;

Nguyen, V. -L. ;

Wang, R. ;

Krysa, G. ;

de Gouville, A. -C. ;

Huet, S. ;

Dodic, N. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (08) :2277-2281

[8] Identification of 1,5-naphthyridine derivatives as a novel series of potent and selective TGF-β type I receptor inhibitors [J].

Gellibert, FO ;

Woolven, J ;

Fouchet, MH ;

Mathews, N ;

Goodland, H ;

Lovegrove, V ;

Laroze, A ;

Nguyen, VL ;

Sautet, S ;

Wang, RL ;

Janson, C ;

Smith, W ;

Krysa, G ;

Boullay, V ;

de Gouville, AC ;

Huet, S ;

Hartley, D .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (18) :4494-4506

[9] Rapid Generation of a High Quality Lead for Transforming Growth Factor-β (TGF-β) Type I Receptor (ALK5) [J].

Goldberg, Frederick W. ;

Ward, Richard A. ;

Powell, Steven J. ;

Debreczeni, Judit E. ;

Norman, Richard A. ;

Roberts, Nicola J. ;

Dishington, Allan P. ;

Gingell, Helen J. ;

Wickson, Kate F. ;

Roberts, Andrew L. .

JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (23) :7901-7905

[10] Pyrazolone based TGFβR1 kinase inhibitors [J].

Guckian, Kevin ;

Carter, Mary Beth ;

Lin, Edward Yin-Shiang ;

Choi, Michael ;

Sun, Lihong ;

Boriack-Sjodin, P. Ann ;

Chuaqui, Claudio ;

Lane, Benjamin ;

Cheung, Kam ;

Ling, Leona ;

Lee, Wen-Cherng .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (01) :326-329

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