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Triazolopyridine JAK Inhibitor Compounds and Methods

a technology of triazolopyridine and jak inhibitor, which is applied in the field of triazolopyridine jak inhibitor compounds and methods, can solve the problems of life-threatening thrombotic events and no known cure for ph mpd diseases, and achieve the effect of lessening the severity and lessening the severity of a diseas

Inactive Publication Date: 2010-02-25
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0013]Another embodiment includes a kit for treating a disease or disorder responsive to the inhibition of a JAK kinase. The kit includes a first pharmaceutical composition comprising a compound of Formula I and instructions for use

Problems solved by technology

If left untreated, both diseases can result in life-threatening thrombotic events.
This primarily leads to splenomegaly, which is followed by anemia in later stages of the disease as hematopoiesis becomes non-productive.
There is no known cure for Ph− MPD diseases.

Method used

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  • Triazolopyridine JAK Inhibitor Compounds and Methods
  • Triazolopyridine JAK Inhibitor Compounds and Methods
  • Triazolopyridine JAK Inhibitor Compounds and Methods

Examples

Experimental program
Comparison scheme
Effect test

example a

JAK2 Inhibition Assay Protocol

[0270]The activity of the isolated JAK2 kinase domain was measured by monitoring phosphorylation of a peptide derived from JAK3 (Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr) fluorescently labeled on the N-terminus with 5-carboxyfluorescein using the Caliper LabChip technology (Caliper Life Sciences, Hopkinton, Mass.). To determine the inhibition constants (Ki) of Examples 1-304, compounds were diluted serially in DMSO and added to 50 μL kinase reactions containing 0.2 nM purified JAK2 enzyme, 100 mM Hepes pH7.2, 0.015% Brij-35, 1.5 μM peptide substrate, 25 μM ATP, 10 mM MgCl2, 4 mM DTT at a final DMSO concentration of 2%. Reactions were incubated at 22° C. in 384-well polypropylene microtiter plates for 30 minutes and then stopped by addition of 25 μL an EDTA containing solution (100 mM Hepes pH 7.2, 0.015% Brij-35, 150 mM EDTA), resulting in a final EDTA concentration of 50 mM. After termination of the kinase reaction, the proportion of phosphoryla...

example b

JAK1 and TYK2 Inhibition Assay Protocol

[0271]The activity of the isolated JAK1 or TYK2 kinase domain was measured by monitoring phosphorylation of a peptide derived from JAK3 (Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr) fluorescently labeled on the N-terminus with 5-carboxyfluorescein using the Caliper LabChip technology (Caliper Life Sciences, Hopkinton, Mass.). To determine the inhibition constants (Ki) of Examples 1-312, compounds were diluted serially in DMSO and added to 50 uL kinase reactions containing 1.5 nM JAK1, 0.2 nM purified JAK2 or 1 nM purified TYK2 enzyme, 100 mM Hepes pH7.2, 0.015% Brij-35, 1.5 uM peptide substrate, 25 uM ATP, 10 mM MgCl2, 4 mM DTT at a final DMSO concentration of 2%. Reactions were incubated at 22° C. in 384-well polypropylene microtiter plates for 30 minutes and then stopped by addition of 25 uL of an EDTA containing solution (100 mM Hepes pH 7.2, 0.015% Brij-35, 150 mM EDTA), resulting in a final EDTA concentration of 50 mM. After terminatio...

example c

JAK3 Inhibition Assay Protocol

[0272]The activity of the isolated JAK3 kinase domain was measured by monitoring phosphorylation of a peptide derived from JAK3 (Leu-Pro-Leu-Asp-Lys-Asp-Tyr-Tyr-Val-Val-Arg) fluorescently labeled on the N-terminus with 5-carboxyfluorescein using the Caliper LabChip technology (Caliper Life Sciences, Hopkinton, Mass.). To determine the inhibition constants (Ki) of Examples 1-312, compounds were diluted serially in DMSO and added to 50 uL kinase reactions containing 5 nM purified JAK3 enzyme, 100 mM Hepes pH7.2, 0.015% Brij-35, 1.5 uM peptide substrate, 5 uM ATP, 10 mM MgCl2, 4 mM DTT at a final DMSO concentration of 2%. Reactions were incubated at 22° C. in 384-well polypropylene microtiter plates for 30 minutes and then stopped by addition of 25 uL of an EDTA containing solution (100 mM Hepes pH 7.2, 0.015% Brij-35, 150 mM EDTA), resulting in a final EDTA concentration of 50 mM. After termination of the kinase reaction, the proportion of phosphorylated ...

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Abstract

A compound of Formula I, enantiomers, diasteriomers, tautomers or pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4 and R5 are defined herein, are useful as JAK kinase inhibitors. A pharmaceutical composition that includes a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant or vehicle, and methods of treating or lessening the severity of a disease or condition responsive to the inhibition of JAK kinase activity in a patient are disclosed.

Description

FIELD OF THE INVENTION[0001]Triazolopyridine compounds of Formula I, which are inhibitors of Janus kinases, for example JAK2 kinase, as well as compositions containing these compounds and methods of use including, but not limited to, in vitro, in situ and in vivo diagnosis or treatment of mammalian cells.BACKGROUND OF INVENTION[0002]Myeloproliferative disorders (MPD) originate in hematopoietic stem cells and primarily manifest in elevated counts of mostly normal cells of the myeloid lineage. A primary distinction between Philadelphia-chromosome positive (Ph+) and Philadelphia-chromosome negative (Ph−) can be made. Ph+ MPD results in chronic myelogenous leukemia and is driven by a bcr-abl fusion protein that drives hematopoietic cell proliferation. Ph− MPD can be further subclassified into three distinct disorders by related varieties, namely polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). Dameshek, W., Blood 6(4):372-375 (1951). Patients wi...

Claims

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Application Information

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IPC IPC(8): A61K31/437C07D471/04A61K31/496A61K31/5377A61P35/00A61P3/10A61P9/00A61P31/12A61P37/00A61P29/00A61P25/00
CPCC07D471/04C07D487/04A61P1/16A61P17/00A61P17/04A61P17/06A61P19/02A61P19/08A61P21/00A61P25/00A61P25/14A61P25/16A61P25/28A61P29/00A61P31/00A61P31/12A61P35/00A61P35/02A61P35/04A61P37/00A61P37/02A61P37/04A61P37/06A61P37/08A61P43/00A61P5/00A61P7/00A61P7/02A61P9/00A61P9/10A61P3/10C07D401/12A61K31/437A61K31/496A61K31/5377
Inventor ZHU, BING-YANSIU, MICHAELMAGNUSON, STEVEN R.PASTOR, RICHARDHAIYING, HEYISONG, XIAOJIFU, ZHENGXING, XUJUNPING, ZHAO
Owner GENENTECH INC
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