Design and synthesis of novel p38α MAP kinase inhibitors: Discovery of pyrazole-benzyl ureas bearing 2-molpholinopyrimidine moiety

被引：14

作者：

Arai, Tadamasa ^{[1
]}

Ohno, Michihiro ^{[1
]}

Inoue, Hideki ^{[1
]}

Hayashi, Shinnosuke ^{[1
]}

Aoki, Takumi ^{[1
]}

Hirokawa, Hiroe ^{[1
]}

Meguro, Hiroyuki ^{[1
]}

Koga, Yoko ^{[1
]}

Oshida, Keiyu ^{[1
]}

Kainoh, Mie ^{[1
]}

Suyama, Kazuharu ^{[1
]}

Kawai, Hideki ^{[1
]}

机构：

[1] Toray Industries Ltd, Pharmaceut Res Labs, Kamakura, Kanagawa 2488555, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 15期

关键词：

Kinase inhibitor; p38; alpha; Pyrazole-benzyl urea; Docking study; Hepatotoxicity; ACTIVATED PROTEIN-KINASE; RHEUMATOID-ARTHRITIS; CROHNS-DISEASE; BIRB-796; AGENTS;

D O I：

10.1016/j.bmcl.2012.05.095

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery that pyrazole-benzyl urea derivatives bearing a 2-molpholinopyrimidine moiety are novel p38 alpha inhibitors is described. A comparative view of the binding modes of SB-203580 and BIRB-796 by structural alignment of two X-ray co-crystal structures was utilized to identify this novel series. Modification of the benzyl group led to compound 2b, a highly potent p38 alpha inhibitor. In in vivo studies, 2b inhibited the production of tumor necrosis factor-alpha in lipopolysaccharide-treated mouse in a dose-dependent manner. Furthermore, the results of a 5-day repeated oral dose toxicity study suggest that 2b has low hepatotoxicity. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：5118 / 5122

页数：5

共 50 条

[1] Discovery and design of novel benzimidazolone as inhibitors of p38 MAP kinase.
Hammach, A
Ralph, M
Corbo, F
Barbosa, A
Liu, PR
Soleymanzadeh, F
Goldberg, D
Sarko, C
Mckibben, B
Moss, N
Hao, MH
White, A
Qian, K
Pargellis, C
Kroe, R
Wildeson, J
Nelson, R
Fadra, T
Capolino, A
Kashem, M
Patnaude, L
Madwed, J
Torcellini, C
Kaplita, P
Farrel, T
Hu, HB
Yazdania, M
Kavanaugh, K
[J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2004, 228 : U947 - U947
[2] Design, synthesis, and SAR of a novel series of p38α MAP kinase inhibitors
Martin, Barrie P.
[J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2011, 241
[3] Discovery and design of benzimidazolone based inhibitors of p38 MAP kinase
Hammach, Abdelhakim
Barbosa, Antonio
Gaenzler, Faith Corbo
Fadra, Tazmeen
Goldberg, Daniel
Hao, Ming-Hong
Kroe, Rachel R.
Liu, Pingrong
Qian, Kevin C.
Ralph, Mark
Sarko, Christopher
Soleymanzadeh, Fariba
Moss, Nell
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (24) : 6316 - 6320
[4] The design and synthesis of novel α-ketoamide-based p38 MAP kinase inhibitors
Montalban, Antonio Garrido
Boman, Erik
Chang, Chau-Dung
Ceide, Susana Conde
Dahl, Russell
Dalesandro, David
Delaet, Nancy G. J.
Erb, Eric
Ernst, Justin T.
Gibbs, Andrew
Kahl, Jeffrey
Kessler, Linda
Lundstroem, Jan
Miller, Stephen
Nakanishi, Hiroshi
Roberts, Edward
Saiah, Eddine
Sullivan, Robert
Wang, Zhijun
Larson, Christopher J.
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (06) : 1772 - 1777
[5] MEDI 369-Novel tricyclic pyrazole inhibitors of p38 map kinase
Virgili, Marina
Almansa, Carmen
Cavalcanti, Fernando L.
[J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2008, 236
[6] Design and synthesis of potent pyridazine inhibitors of p38 MAP kinase
Tamayo, N
Liao, L
Goldberg, M
Powers, D
Tudor, YY
Yu, V
Wong, LM
Henkle, B
Middleton, S
Syed, R
Harvey, T
Jang, G
Hungate, R
Dominguez, C
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (09) : 2409 - 2413
[7] Design, Synthesis and Characterization of N′,N"-Diaryl Ureas as p38 Kinase Inhibitors
Kulkarni, Ravindra G.
Laufer, Stefan
Mangannavar, Chandrashekhar
Garlapati, Achaiah
[J]. MEDICINAL CHEMISTRY, 2013, 9 (02) : 213 - 221
[8] P38 α map kinase inhibitors:: From discovery to the clinic
Dugar, S
Mavunkel, B
Chakravarty, S
Perumattam, J
Luedtke, G
Lu, Q
Chen, Z
Xu, YJ
Protter, A
Schreiner, G
Almirez, R
Scott, B
Laney, M
Henson, M
Lewicki, J
Moore, A
Lee, S
Brahn, E
Liu, D
[J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2005, 229 : U162 - U162
[9] Novel inhibitors of p38 MAP kinase.
Shetty, R
Moffett, KK
Nguyen, D
Kelly, MJ
Michelotti, EL
Dorsey, BD
Springman, E
Bukhtiyarova, M
Northrop, K
Chai, XM
Saporito, MS
Ochman, AR
Karpusas, M
[J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2004, 228 : U947 - U947
[10] N-phenyl-N-purin-6-yl ureas:: The design and synthesis of P38α MAP kinase inhibitors
Wan, ZH
Boehm, JC
Bower, MJ
Kassis, S
Lee, JC
Zhao, BG
Adams, JL
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (06) : 1191 - 1194

← 1 2 3 4 5 →