5-Aminomethylbenzimdazoles as potent ITK antagonists

被引：33

作者：

Riether, Doris ^{[1
]}

Zindell, Renee ^{[1
]}

Kowalski, Jennifer A. ^{[1
]}

Cook, Brian N. ^{[1
]}

Bentzien, Joerg ^{[1
]}

De Lombaert, Stephane ^{[1
]}

Thomson, David ^{[1
]}

Kugler, Stanley Z., Jr. ^{[1
]}

Skow, Donna ^{[1
]}

Martin, Leslie S. ^{[1
]}

Raymond, Ernest L. ^{[2
,3
]}

Khine, Hnin Hnin

O'Shea, Kathy ^{[2
,3
]}

Woska, Joseph R., Jr. ^{[2
,3
]}

Jeanfavre, Deborah ^{[2
,3
]}

Sellati, Rosemarie ^{[2
,3
]}

Ralph, Kerry L. M. ^{[2
,3
]}

Ahlberg, Jennifer ^{[5
]}

Labissiere, Gabriel ^{[5
]}

Kashem, Mohammed A. ^{[1
]}

Pullen, Steven S. ^{[4
]}

Takahashi, Hidenori ^{[1
]}

机构：

[1] Boehringer Ingelheim Pharmaceut Inc, Dept Med Chem, Ridgefield, CT 06877 USA

[2] Boehringer Ingelheim Pharmaceut Inc, Dept Inflammat, Ridgefield, CT 06877 USA

[3] Boehringer Ingelheim Pharmaceut Inc, Dept Immunol, Ridgefield, CT 06877 USA

[4] Boehringer Ingelheim Pharmaceut Inc, Dept Cardiovasc Dis, Ridgefield, CT 06877 USA

[5] Boehringer Ingelheim Pharmaceut Inc, Dept Drug Discovery Support, Ridgefield, CT 06877 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 06期

关键词：

ITK; Interleukin-2 inducible T-cell kinase; 5-Aminobenzimidazole; CELL KINASE ITK; TEC FAMILY; INHIBITORS; DISCOVERY;

D O I：

10.1016/j.bmcl.2009.02.012

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Benzamide 1 demonstrated good potency as a selective ITK inhibitor, however the amide moiety was found to be hydrolytically labile in vivo, resulting in low oral exposure and the generation of mutagenic aromatic amine metabolites. Replacing the benzamide with a benzylamine linker not only addressed the toxicity issue, but also improved the cellular and functional potency as well as the drug-like properties. SAR studies around the benzylamines and the identification of 10n and 10o as excellent tools for proof-of-concept studies are described. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：1588 / 1591

页数：4

共 11 条

[1] Discovery of potent inhibitors of interleukin-2 inducible T-cell kinase (ITK) through structure-based drug design [J].

Cook, Brian N. ;

Bentzien, Joerg ;

White, Andre ;

Nemoto, Peter A. ;

Wang, Ji ;

Man, Chuk C. ;

Soleymanzadeh, Fariba ;

Khine, Hnin Hnin ;

Kashem, Mohammed A. ;

Kugler, Stanley Z., Jr. ;

Wolak, John P. ;

Roth, Gregory P. ;

De Lombaert, Stephane ;

Pullen, Steven S. ;

Takahashi, Hidenori .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (03) :773-777

[2] Impaired NFATc translocation and failure of Th2 development in Itk-deficient CD4+ T cells [J].

Fowell, DJ ;

Shinkai, K ;

Liao, XC ;

Beebe, AM ;

Coffman, RL ;

Littman, DR ;

Locksley, RM .

IMMUNITY, 1999, 11 (04) :399-409

[3] 5-HETEROARYL-2-THIOPHENECARBOXYLIC ACIDS - OXAZOLES AND OXADIAZOLES [J].

GODDARD, CJ .

JOURNAL OF HETEROCYCLIC CHEMISTRY, 1991, 28 (01) :17-28

[4] Altering T-cell activation by targeting the multidomain tyrosine kinase Itk [J].

Kanner, SB ;

Perez-Villar, JJ .

TRENDS IN IMMUNOLOGY, 2003, 24 (05) :249-253

[5] Three mechanistically distinct kinase assays compared: Measurement of intrinsic ATPase activity identified the most comprehensive set of ITK inhibitors [J].

Kashem, Mohammed A. ;

Nelson, Richard M. ;

Yingling, Jeffrey D. ;

Pullen, Steven S. ;

Prokopowicz, Anthony S., III ;

Jones, Jessi Wildeson ;

Wolak, John P. ;

Rogers, George R. ;

Morelock, Maurice M. ;

Snow, Roger J. ;

Homon, Carol Ann ;

Jakes, Scott .

JOURNAL OF BIOMOLECULAR SCREENING, 2007, 12 (01) :70-83

[6] Requirement for Tec kinases Rlk and Itk in T cell receptor signaling and immunity [J].

Schaeffer, EM ;

Debnath, J ;

Yap, G ;

McVicar, D ;

Liao, XC ;

Littman, DR ;

Sher, A ;

Varmus, HE ;

Lenardo, MJ ;

Schwartzberg, PL .

SCIENCE, 1999, 284 (5414) :638-641

[7] Mutation of Tec family kinase alters T helper cell differentiation [J].

Schaeffer, EM ;

Yap, GS ;

Lewis, CM ;

Czar, MJ ;

McVicar, DW ;

Cheever, AW ;

Sher, A ;

Schwartzberg, PL .

NATURE IMMUNOLOGY, 2001, 2 (12) :1183-1188

[8] The Tec family of cytoplasmic tyrosine kinases: mammalian Btk, Bmx, Itk, Tec, Txk and homologs in other species [J].

Smith, CIE ;

Islam, TC ;

Mattsson, PT ;

Mohamed, AJ ;

Nore, BF ;

Vihinen, M .

BIOESSAYS, 2001, 23 (05) :436-446

[9] Hit-to-lead studies on benzimidazole inhibitors of ITK: Discovery of a novel class of kinase inhibitors [J].

Snow, Roger J. ;

Abeywardane, Asitha ;

Campbell, Scot ;

Lord, John ;

Kashem, Mohammed A. ;

Khine, Hnin Hnin ;

King, Josephine ;

Kowalski, Jennifer A. ;

Pullen, Steven S. ;

Roma, Teresa ;

Roth, Gregory P. ;

Sarko, Christopher R. ;

Wilson, Noel S. ;

Winters, Michael P. ;

Wolak, John P. ;

Cywin, Charles L. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (13) :3660-3665

[10]

WHITE A, J BIOL CHEM UNPUB

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