Triazole-derived kinase inhibitors and uses thereof

a kinase inhibitor and triazole technology, applied in the field of medical chemistry, can solve the problems of insufficient treatment options and unclear whether these compounds have the appropriate pharmacological profiles to be therapeutically useful, and achieve the effect of inhibiting the activity of the enzyme and facilitating the treatment or prophylaxis of diseases

Inactive Publication Date: 2005-12-08
HALE MICHAEL R +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is not clear whether these compounds have the appropriate pharmacological profiles to be therapeutically useful.
For many of these conditions the currently available treatment options are inadequate.

Method used

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  • Triazole-derived kinase inhibitors and uses thereof
  • Triazole-derived kinase inhibitors and uses thereof
  • Triazole-derived kinase inhibitors and uses thereof

Examples

Experimental program
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Effect test

example 1

ERK Inhibition Assay

[0132] Compounds are assayed for the inhibition of ERK2 by a spectrophotometric coupled-enzyme assay (Fox et al (1998) Protein Sci 7, 2249). In this assay, a fixed concentration of activated ERK2 (10 nM) is incubated with various concentrations of the compound in DMSO (2.5%) for 10 min. at 30° C. in 0.1 M HEPES buffer, pH 7.5, containing 10 mM MgCl2, 2.5 mM phosphoenolpyruvate, 200 μM NADH, 150 μg / mL pyruvate kinase, 50 μg / mL lactate dehydrogenase, and 200 μM erktide peptide. The reaction is initiated by the addition of 65 μM ATP. The rate of decrease of absorbance at 340 nm is monitored, which indicates the extent of uninhibited enzyme present in the assay. The IC50 is evaluated from the rate data as a function of inhibitor concentration.

example 2

ERK Inhibition Cell Proliferation Assay

[0133] Compounds may be assayed for the inhibition of ERK2 by a cell proliferation assay. In this assay, a complete media is prepared by adding 10% fetal bovine serum and penicillin / streptomycin solution to RPMI 1640 medium (JRH Biosciences). Colon cancer cells (HT-29 cell line) are added to each of 84 wells of a 96 well plate at a seeding density of 10,000 cells / well / 150 μL. The cells are allowed to attach to the plate by incubating at 37° C. for 2 hours. A solution of test compound is prepared in complete media by serial dilution to obtain the following concentrations: 20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, and 0.08 μM. The test compound solution (50 μL) is added to each of 72 cell-containing wells. To the 12 remaining cell-containing wells, only complete media (200 μL) is added to form a control group in order to measure maximal proliferation. To the remaining 12 empty wells, complete media is added to form a vehicle control group in ord...

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Abstract

Described herein are compounds that are useful as protein kinase inhibitors having the formula: where Ht, R2, T, and m are as described in the specification. The compounds are useful for treating diseases in mammals that are alleviated by a protein kinase inhibitor, particularly diseases such as cancer, inflammatory disorders, restenosis, and cardiovascular disease.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application 60 / 287,204, filed Apr. 27, 2001, the contents of which are incorporated herein by reference.TECHNICAL FIELD OF THE INVENTION [0002] The present invention is in the field of medicinal chemistry and relates to triazole compounds that are protein kinase inhibitors, especially inhibitors of ERK, compositions containing such compounds and methods of use. The compounds are useful for treating cancer and other diseases that are alleviated by protein kinase inhibitors. BACKGROUND OF THE INVENTION [0003] Mammalian mitogen-activated protein (MAP) kinases are serine / threonine kinases that mediate intracellular signal transduction pathways (Cobb and Goldsmith, 1995, J. Biol. Chem., 270, 14843; Davis, 1995, Mol. Reprod. Dev. 42, 459). Members of the MAP kinase family share sequence similarity and conserved structural domains, and include the ERK2 (extracellular signal regulated kinase)...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4192A61K31/4196A61K31/428A61K31/4439A61K31/506A61K31/5377A61K45/00A61P1/16A61P3/10A61P5/00A61P7/02A61P9/00A61P9/04A61P9/10A61P11/00A61P17/06A61P19/08A61P21/00A61P25/00A61P25/08A61P25/14A61P25/16A61P25/28A61P29/00A61P31/04A61P31/12A61P35/00A61P35/02A61P37/04A61P37/06A61P37/08A61P43/00C07D249/06C07D249/08C07D249/10C07D401/14C07D403/04C07D403/14C07D405/14C07D417/14C07D521/00
CPCC07D231/12C07D233/56C07D249/06C07D249/08C07D249/10C07D401/14C07D403/04C07D403/14C07D405/14C07D417/14A61P1/16A61P3/10A61P5/00A61P7/02A61P9/00A61P9/04A61P9/10A61P11/00A61P17/06A61P19/08A61P21/00A61P25/00A61P25/08A61P25/14A61P25/16A61P25/28A61P29/00A61P31/04A61P31/12A61P35/00A61P35/02A61P37/04A61P37/06A61P37/08A61P43/00
Inventor HALE, MICHAEL R.MALTAIS, FRANCOIS
Owner HALE MICHAEL R
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