Treatment of fibroproliferative disorders using TGF-beta inhibitors

• US 20040038856A1
• Filed: 05/16/2003
• Published: 02/26/2004
• Est. Priority Date: 05/17/2002
• Status: Abandoned Application

• Current Assignee: Scios, Inc. (Johnson & Johnson)
• Original Assignee: Scios, Inc. (Johnson & Johnson)
• Inventors: Tran, Thomas-Toan, Liu, David Y., Chakravarty, Sarvajit, Dugar, Sundeep, Schreiner, George F., Protter, Andrew A., Higgins, Linda S., Kapoun, Ann M.
• Application Number:
  US10/440,428
• Publication Number:
  US 20040038856A1
• Time in Patent Office: Days
• US Class Current: 514/1
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495

Abstract

The invention concerns methods of treating fibroproliferative disorders associated with TGF-β signaling, by administering non-peptide small molecule inhibitors of TGF-β specifically binding to the type I TGF-β receptor (TGFβ-R1). Preferably, the inhibitors are quinazoline derivatives. The invention also concerns methods for reversing the effect of TGF-β-mediated cell activation on the expression of a gene associated with fibrosis, comprising contacting a cell or tissue in which the expression of such gene is altered as a result of TGF-β-mediated cell activation, with a non-peptide small molecule inhibitor of TGF-β, specifically binding a TGFβ-R1 receptor kinase present in the cell or tissue.

Claims

1. A method for the treatment of a fibroproliferative disease, comprising

(a) identifying a non-peptide small molecule, selectively binding to a TGFβ

-R1 kinase receptor; and

(b) administering an effective amount of said molecule to a mammalian subject diagnosed with said fibroproliferative disease.

2. The method of claim 1 wherein said fibroproliferative disease is a renal, hepatic, pulmonary, cardiovascular, eye, or dermatological disorder associated with enhanced TGF-β

activity and excessive fibrosis or sclerosis.

3. The method of claim 1 wherein said fibroproliferative disease is selected from the group consisting of glomerulonephritis (GN);

diabetic nephropathy;

renal interstitial fibrosis;

renal fibrosis resulting from complications of drug exposure;

HIV-associated nephropathy;

transplant necropathy;

liver cirrhosis due to all etiologies;

disorders of the biliary tree;

hepatic dysfunction attributable to infections;

pulmonary fibrosis;

adult respiratory distress syndrome (ARDS);

chronic obstructive pulmonary disease (COPD);

idiopathic pulmonary fibrosis (IPF);

acute lung injury (ALI);

pulmonary fibrosis due to infectious or toxic agents;

congestive heart failure;

dilated cardiomyopathy;

myocarditis;

vascular stenosis;

progressive systemic sclerosis;

polymyositis;

scleroderma;

dermatomyositis;

fascists;

Raynaud'"'"'s syndrome, rheumatoid arthritis;

proliferative vitreoretinopathy;

fibrosis associated with ocular surgery; and

excessive or hypertrophic scar or keloid formation in the dermis occurring during wound healing resulting from trauma or surgical wounds.

4. The method of claim 1 wherein said molecule additionally inhibits a biological activity mediated by p38 kinase.

5. The method of claim 1 wherein said molecule preferentially inhibits a biological activity mediated by TGF-β

-RI kinase relative to a biological activity mediated by p38 kinase.

6. The method of claim 1 wherein said molecule is a compound of formula (1)

7. The method of claim 6 wherein said compound is a quinazoline derivative.

8. The method of claim 7 wherein Z³ is N;

and Z⁵-Z⁸ are CR².

9. The method of claim 7 wherein Z³ is N;

and at least one of Z⁵-Z⁸ is nitrogen.

10. The method of claim 7 wherein R³ is an optionally substituted phenyl moiety.

11. The method of claim 10 wherein R³ is selected from the group consisting of 2-, 4-, 5-, 2,4- and 2,5-substituted phenyl moieties.

12. The method of claim 11 wherein at least one substituent of said phenyl moiety is an alkyl(1-6C), or halo.

13. The method of claim 1 wherein said molecule is a compound of formula (2)

14. A method for reversing the effect of TGF-β

-mediated cell activation on the expression of a gene associated with fibrosis, comprising contacting a cell or tissue in which the expression of said gene is altered as a result of TGF-β

-mediated cell activation, with a non-peptide small molecule inhibitor of TGF-β

, specifically binding a TGFβ

-R1 receptor kinase present in said cell or tissue.

15. The method of claim 14 wherein said gene is associated with fibrosis.

16. The method of claim 15 wherein said gene is overexpressed as a result of TGF-β

-mediated cell activation.

17. The method of claim 16 wherein said gene is selected from the group consisting of fibronectin, collagen, type I, alpha 2 COL1A2);

collagen, type V, alpha 2 (COL5A2);

connective tissue growth factor (CTGF);

thrombospondin 1 (THBS

     1);

hexabrachion (HXB);

tissue inhibitor of metalloproteinase 1 (TIMP-1);

tissue inhibitor of metalloproteinase 3 (TIMP3);

plasminogen activator inhibitor-1 (PAI-1); and

collagen, type III, alpha 1 (COL3A1).

18. The method of claim 17 wherein said inhibitor reverses the effect of TGF-β

-mediated cell activation on the expression of two or more of said genes.

19. The method of claim 18 wherein said gene is underexpressed as a result of TGF-β

-mediated cell activation.

20. The method of claim 19 wherein said gene is platelet-derived growth factor receptor-α

(PDGFRα

).

21. The method of claim 20 wherein said inhibitor reverses the effect of TGF-β

-mediated cell activation on the expression of two or more of said genes.

22. The method of claim 21 wherein said tissue is selected from the group consisting of lung tissue, heart tissue, liver tissue, and kidney tissue.

23. The method of claim 22 wherein said inhibitor reverses the effect of TGF-β

-mediated cell activation on a multiplicity of genes associated with fibrosis.

24. The method of claim 14 wherein said inhibitor additionally blocks biological activities mediated by Smad proteins, p38 and TAK1.

25. The method of claim 14 wherein said inhibitor is of the formula

26. The method of claim 25 wherein said compound is a quinazoline derivative.

27. The method of claim 26 wherein Z³ is N;

and Z⁵-Z⁸ are CR².

28. The method of claim 27 wherein Z³ is N;

and at least one of Z⁵-Z⁸is nitrogen.

29. The method of claim 27 wherein R³ is an optionally substituted phenyl moiety.

30. The method of claim 29 wherein R³ is selected from the group consisting of 2-, 4-, 5-, 2,4- and 2,5-substituted phenyl moieties.

31. The method of claim 30 wherein at least one substituent of said phenyl moiety is an alkyl(1-6C), or halo.

32. The method of claim 14 wherein said molecule is a compound of formula (2)

33. A method for determining the likelihood of a positive response of a subject diagnosed with a fibroproliferative disease associated with TGF-β

-mediated cell activation to treatment with a TGF-β

inhibitor specifically binding the TGFβ

-R1 receptor, comprising

(a) determining in a biological sample obtained from said subject the expression level of one or more genes selected from the group consisting of fibronectin (FN), collagen, type I, alpha 2 COL1A2);

collagen, type V, alpha 2 (COL5A2);

connective tissue growth factor (CTGF);

thrombospondin 1 (THBS

     1);

hexabrachion (HXB);

tissue inhibitor of metalloproteinase 1 (TIMP-1);

tissue inhibitor of metalloproteinase 3 (TIMP3);

plasminogen activator inhibitor-1 (PAI-1);

platelet-derived growth factor receptor-α

(PDGFRα

);

glucocorticoid receptor (GR);

Smad2;

Smad3;

Smad4;

Smad7;

Col 1;

Col 3;

TGF-β

activated kinase (TAKI);

p38 alpha;

β

-actin;

Cox1;

Cox 2;

I kappa-B kinase (iKKi); and

collagen, type III, alpha-1 (COL3A1), compared with expression in a sample obtained from a normal subject; and

(b) indicating a positive response, if one or more of said genes are differentially expressed.

34. The method of claim 33 wherein a positive response is indicated if one or more genes selected from the group consisting of fibronectin (FN), collagen, type I, alpha 2 (COL1A2);

collagen, type V, alpha 2 (COL5A2);

connective tissue growth factor (CTGF);

thrombospondin 1 (THBS

     1);

hexabrachion (HXB);

tissue inhibitor of metalloproteinase 1 (TIMP-1);

tissue inhibitor of metalloproteinase 3 (TIMP3);

plasminogen activator inhibitor-1 (PAI-1);

Smad7;

Col 1;

interleukin-6 (IL-6);

Cox1;

Cox2; and

collagen, type III, alpha 1 (COL3A1) are overexpressed.

35. The method of claim 33 wherein a positive response is indicated if one or more of genes selected from the group consisting of platelet-derived growth factor receptor-α

(PDGFRα

);

glucocorticoid receptor (GR);

Smad3; and

I kappa-B kinase (iKKi) are underexpressed.

36. The method of claim 33 wherein said fibroproliferative disease is selected from the group consisting of glomerulonephritis (GN);

diabetic nephropathy;

renal interstitial fibrosis;

renal fibrosis resulting from complications of drug exposure;

HIV-associated nephropathy;

transplant necropathy;

liver cirrhosis due to all etiologies;

disorders of the biliary tree;

hepatic dysfunction attributable to infections;

pulmonary fibrosis;

adult respiratory distress syndrome (ARDS);

chronic obstructive pulmonary disease (COPD);

idiopathic pulmonary fibrosis (TPF);

acute lung injury (ALI);

congestive heart failure;

dilated cardiomyopathy;

myocarditis;

vascular stenosis;

progressive systemic sclerosis;

polymyositis;

scleroderma;

dermatomyositis;

fascists;

Raynaud'"'"'s syndrome, rheumatoid arthritis;

proliferative vitreoretinopathy;

fibrosis associated with ocular surgery; and

excessive or hypertrophic scar or keloid formation in the dermis occurring during wound healing resulting from trauma or surgical wounds.

37. A method of diagnosing a patient with a fibroproliferative disease, comprising

(a) determining in a biological sample obtained from said patient the expression level of one or more genes selected from the group consisting of fibronectin, collagen, type I, alpha 2 (COL1A2);

collagen, type V, alpha 2 (COL5A2);

connective tissue growth factor (CTGF);

thrombospondin 1 (THBS1);

hexabrachion (HXB);

tissue inhibitor of metalloproteinase 1 (TIMP-1);

tissue inhibitor of metalloproteinase 3 (TIMP3);

plasminogen activator inhibitor-1 (PAI-1);

collagen, type III, alpha 1 (COL3A1);

glucocorticoid receptor (GR);

Smad2;

Smad3;

Smad4;

Smad7;

Col 1;

Col 3;

TGF-β

activated kinase (TAKI);

p38 alpha;

β

-actin;

Cox1;

Cox 2;

I kappa-B kinase (iKKi); and

platelet-derived growth factor receptor-α

(PDGFRα

), compared with expression in a normal sample; and

(b) diagnosing said patient with a fibroproliferative disease if one or more of said genes are differentially expressed.

38. The method of claim 37 wherein said patient is diagnosed with said fibroproliferative disease if one or more genes selected from the group consisting of fibronectin (FN), collagen, type I, alpha 2 (COL1A2);

collagen, type V, alpha 2 (COL5A2);

connective tissue growth factor (CTGF);

thrombospondin 1 (THBS1);

hexabrachion (HXB);

tissue inhibitor of metalloproteinase 1 (TIMP-1);

tissue inhibitor of metalloproteinase 3 (TIMP3);

plasminogen activator inhibitor-1 (PAI-1);

Smad7;

Col 1;

interleukin-6 (IL-6);

Cox1;

Cox2; and

collagen, type III, alpha-1 are overexpressed.

39. The method of claim 37 wherein said patient is diagnosed with a fibroproliferative disease if one or more of genes selected from the group consisting of platelet-derived growth factor receptor-α

(PDGFRα

);

glucocorticoid receptor (GR);

Smad3; and

I kappa-B kinase (iKKi) are underexpressed.

40. A method of treating a fibroproliferative disease in a subject, comprising administering to the subject dexamethasone and a TGF-β

inhibitor, specifically binding a TGFβ

-R1 receptor.

41. The method of claim 40 wherein the fibroproliferative disease is a renal, hepatic, pulmonary, cardiovascular, eye, or dermatological disorder associated with enhanced TGF-β

activity and excessive fibrosis or sclerosis.

42. The method of claim 40 wherein said fibroproliferative disease is selected from the group consisting of glomerulonephritis (GN);

diabetic nephropathy;

renal interstitial fibrosis;

renal fibrosis resulting from complications of drug exposure;

HIV-associated nephropathy;

transplant necropathy;

liver cirrhosis due to all etiologies;

disorders of the biliary tree;

hepatic dysfunction attributable to infections;

pulmonary fibrosis;

adult respiratory distress syndrome (ARDS);

chronic obstructive pulmonary disease (COPD);

idiopathic pulmonary fibrosis (IPF);

acute lung injury (ALI);

pulmonary fibrosis due to infectious or toxic agents;

congestive heart failure;

dilated cardiomyopathy;

myocarditis;

vascular stenosis;

progressive systemic sclerosis;

polymyositis;

scleroderma;

dermatomyositis;

fascists;

Raynaud'"'"'s syndrome, rheumatoid arthritis;

proliferative vitreoretinopathy;

fibrosis associated with ocular surgery; and

excessive or hypertrophic scar or keloid formation in the dermis occurring during wound healing resulting from trauma or surgical wounds.

43. The method of claim 40 wherein the subject is human.

44. The method of claim 43 wherein said TGF-β

inhibitor is a compound of formula (1)

45. The method of claim 43 wherein said TGF-β

inhibitor if a compound of formula (2)