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Pyrazolopyrimidine jak inhibitor compounds and methods

a technology of pyrazolopyrimidine and inhibitor compounds, applied in the field of p, can solve the problems of life-threatening thrombotic events, no known cure for ph-mpd diseases, etc., and achieve the effect of lessening the severity of a diseas

Inactive Publication Date: 2014-04-17
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The pyrazolopyrimidine compounds effectively inhibit JAK kinases, providing therapeutic benefits for patients with JAK2-driven myeloproliferative disorders and other conditions by modulating JAK2 kinase activity, thereby alleviating symptoms and potentially halting disease progression.

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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  • Pyrazolopyrimidine jak inhibitor compounds and methods
  • Pyrazolopyrimidine jak inhibitor compounds and methods
  • Pyrazolopyrimidine jak inhibitor compounds and methods

Examples

Experimental program
Comparison scheme
Effect test

example a

JAK2 Inhibition Assay Protocol

[0310]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), 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 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 product was...

example b

JAK1 and TYK2 Inhibition Assay Protocol

[0311]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 inhibition constants (Ki), 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 termination of the kinase reacti...

example c

JAK3 Inhibition Assay Protocol

[0312]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 inhibition constants (Ki), 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 product was determined...

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PUM

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Abstract

The invention provides JAK kinase inhibitors of Formula Ia, enantiomers, diasteriomers or pharmaceutically acceptable salts thereof, wherein R1, R2, R7 and Z are defined herein, a pharmaceutical composition that includes a compound of Formula Ia 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 a JAK kinase activity in a patient.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. Ser. No. 13 / 099,179, filed on May 2, 2011, which is a continuation of International Application No. PCT / US2009 / 063014, filed on Nov. 2, 2009, which claims the benefit of U.S. Ser. No. 61 / 110,497, filed on Oct. 31, 2008, all of which are incorporated by reference herein in their entirety.FIELD OF THE INVENTION[0002]Pyrazolopyrimidine compounds, inhibitors of JAK kinases, 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[0003]Cytokine pathways mediate a broad range of biological functions, including many aspects of inflammation and immunity. Janus kinases (JAK), including JAK1, JAK2, JAK3 and TYK2 are cytoplasmic protein kinases that associate with type I and type II cytokine receptors and regulate cytokine signal transduction. Cytokine engagement with c...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D487/04
CPCC07D487/04A61P1/16A61P11/06A61P17/00A61P17/06A61P19/00A61P25/00A61P25/28A61P29/00A61P31/00A61P31/12A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P5/00A61P7/02A61P9/00A61P9/10A61P3/10A61K31/4184A61K31/519
Inventor BLANEY, JEFFREYGIBBONS, PAUL A.HANAN, EMILYLYSSIKATOS, JOSEPH P.MAGNUSON, STEVEN R.PASTOR, RICHARDRAWSON, THOMAS E.ZHOU, AIHEZHU, BING-YAN
Owner GENENTECH INC
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