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Pyrazolopyridines and methods of making and using the same

A technology for medicinal salts and compounds, applied in the fields of pyrazolopyridine and its preparation and use, can solve problems such as inability to bind to TGFβ receptors and lack of biological activity

Inactive Publication Date: 2005-11-09
BIOGEN IDEC MA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The LAP-TGFβ complex cannot bind to the TGFβ receptor and has no biological activity

Method used

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  • Pyrazolopyridines and methods of making and using the same
  • Pyrazolopyridines and methods of making and using the same
  • Pyrazolopyridines and methods of making and using the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] 4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-pyrimidin-2-ylamine

[0107] The synthesis of the title compound is described in Sections (a)-(F) below.

[0108] (a) 2-Methyl-6-trimethylsilylethynyl-pyridine

[0109] Anhydrous triethylamine (45mL), PdCl 2 (PPh 3 ) 2 (0.48 mmol) and copper(I) iodide (1.45 mmol) were added to a solution of 6-bromo-2-picoline (48.2 mmol) in anhydrous DMF (110 mL). To the resulting orange solution was added dropwise (trimethylsilyl)acetylene (62.6 mmol). After stirring overnight at room temperature, the reaction was concentrated in vacuo and diluted with ether (100 mL), hexanes (100 mL) and water (100 mL). The emulsion was filtered through Celite pad and rinsed with ether. The separated organic phase was washed with water (1x), dried (MgSO 4 ) and concentrated in vacuo to afford 8.86 g of a dark brown oil identified as 2-methyl-6-trimethylsilylethynyl-pyridine. 1 H NMR (CDCl 3 , 400MHz): 0.24(s, 9H), 2.53(s, 3H), 7.06(d, ...

Embodiment 2

[0122] A cell-free assay to evaluate inhibition of TGFβ type I receptor autophosphorylation.

[0123] Determination of serine-threonine kinase activity of TGFβ type I receptors containing an N-terminal polyhistidine, TEV cleavage site marker, e.g., histidine-TGFβRI, as the autophosphorylation activity of the cytoplasmic domain of the receptor . The cytoplasmic kinase domain of the His-tagged receptor was purified from infected insect cell cultures using the Gibco-BRL FastBac HTb Baculovirus Population Expression System.

[0124] Assay buffer (50mM Hepes, 60mM NaCl, 1mM MgCl 2 , 2mM DTT, 5mM MnCl 2 , 2% glycerol and 0.015% Brij 35) in 20 μl 1.25 μCi 33 P-ATP / 25 μM ATP was added to a 96-well Nickel FlashPlate (NEN Life Science, Perkin Elmer). 10 [mu]l of the test compound of formula (I) in 5% DMSO solution was added to the FlashPlate. The assay was initiated by adding 20 μl of assay buffer containing 12.5 pmol of His-TGFβRI to each well. Plates were incubated at room tempe...

Embodiment 3

[0128] Cell-free Assay for Evaluating Inhibition of Activin Type I Receptor Kinase Activity

[0129] According to the method similar to the above-mentioned Example 2, replace His-TGFβRI with similar His-tagged Alk4 (His-Alk4), and the autophosphorylation activity of the test compound of formula (I) on activin type I receptor (Alk4) kinase can be determined inhibitory effect.

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Abstract

Compounds of formula I possess unexpectedly high affinity for Alk 5 and / or Alk 4, and can be useful as antagonists thereof for preventing and / or treating numerous diseases, including fibrotic disorders. In one embodiment, the invention features a compound of formula I.

Description

[0001] This non-provisional application claims priority to US Provisional Application 60 / 408,811, filed September 6,2002. Background of the invention [0002] TGFβ (transforming growth factor β) is a member of a large family of dimeric polypeptide growth factors, including activins, inhibins, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and Muller Inhibitor (MIS). There are 3 subtypes of TGFβ (TGFβ1, TGFβ2 and TGFβ3), and exist together with their receptors in most cells. The various isoforms are expressed in a tissue-specific and developmentally regulated manner. The various TGFβ isoforms are synthesized from precursor proteins that are cleaved intracellularly into a C-terminal region (latent activity-associated peptide (LAP)) and an N-terminal region considered to be mature or active TGFβ. LAP is normally non-covalently linked to mature TGFβ prior to secretion from cells. The LAP-TGFβ complex cannot bind to the TGFβ receptor and has no bio...

Claims

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Application Information

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IPC IPC(8): A01N43/00A61K31/415A61K31/445A61K31/535C07D237/00C07D239/00C07D471/04C07D487/04
CPCC07D471/04C07D487/04A61P1/16A61P11/00A61P13/12A61P17/02A61P19/00A61P19/04A61P21/00A61P27/02A61P3/00A61P35/00A61P35/04A61P43/00A61P5/00A61P9/00
Inventor 李文成玛丽·B·卡特孙立红保罗·莱恩克劳迪奥·丘亚奎郑中立贾斯温德·辛葆拉·博里亚克-肖丁
Owner BIOGEN IDEC MA INC
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