Plasminogen activator inhibitor-1 inhibitors and methods of use thereof to modulate lipid metabolism

Patent metadata

Field	Value
Publication number	US-9527878-B2
Application number	US-201514817690-A
Country	US
Kind code	B2
Filing date	Aug 4, 2015
Priority date	Apr 16, 2007
Publication date	Dec 27, 2016
Grant date	Dec 27, 2016

Abstract

The invention relates to plasminogen activator-1 (PAI-1) inhibitor compounds and uses thereof in the treatment of any disease or condition associated with elevated PAI-1. The invention includes, but is not limited to, the use of such compounds to modulate lipid metabolism and treat conditions associated with elevated PAI-1, cholesterol, or lipid levels.

First claim

What is claimed is:

1. A compound having a formula selected from the group consisting of CVIII, CXXIV, CXXV, CXLIII, CXLIV, CXLV, CLI, CLII, CLIII, CLIV, CLV, CLXVIII, CLXXVII, CLXXIX, CLXXX, and salts, esters, or prodrugs thereof:

2. A compound of formula CXLVI or a salt, ester, or prodrug thereof:

wherein R a is C 3 to C 12 alkyl.

3. A method of increasing circulating high density lipoprotein (HDL) in a subject, comprising administering to said subject a plasminogen activator inhibitor-1 (PAI-1) inhibitor compound according to claim 1 in an amount effective to increase HDL.

4. A method of decreasing circulating very low density lipoprotein (VLDL) in a subject, comprising administering to said subject a plasminogen activator inhibitor-1 (PAI-1) inhibitor compound according to claim 1 in an amount effective to decrease VLDL.

5. The method of claim 3 , wherein the subject is human.

6. The method of claim 3 , wherein the PAI-1 inhibitor decreases PAI-1 binding to apolipoprotein E (ApoE), apolipoprotein A (ApoA), and/or VLDL.

7. The method of claim 3 , wherein the PAI-1 inhibitor binds to PAI-1 in the presence of vitronectin and/or urokinase type plasminogen activator (uPA).

8. A method of modulating cholesterol and/or lipid uptake comprising the step of administering a PAI-1 inhibitor compound according to claim 1 in an amount effective to modulate cholesterol and/or lipid uptake.

9. A method of modulating cholesterol and/or lipid clearance comprising the step of administering a plasminogen activator inhibitor-1 (PAI-1) inhibitor compound according to claim 1 in an amount effective to inhibit very low density lipoprotein (VLDL) or apolipoprotein E (ApoE) or apolipoprotein A (ApoA) binding to VLDL-R and modulate cholesterol and/or lipid clearance.

10. A method of modulating cholesterol and/or lipid clearance comprising the step of administering a plasminogen activator inhibitor-1 (PAI-1) inhibitor compound according to claim 1 in an amount effective to affect HDL or apolipoprotein E (ApoE) or apolipoprotein A (ApoA) binding to an ApoA receptor and modulate cholesterol and/or lipid clearance.

11. A composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.

12. The method of claim 4 , wherein the subject is human.

13. The method of claim 4 , wherein the PAI-1 inhibitor decreases PAI-1 binding to apolipoprotein E (ApoE), apolipoprotein A (ApoA), and/or VLDL.

14. The method of claim 4 , wherein the PAI-1 inhibitor binds to PAI-1 in the presence of vitronectin and/or urokinase type plasminogen activator (uPA).

15. A method of increasing circulating high density lipoprotein (HDL) in a subject, comprising administering to said subject a plasminogen activator inhibitor-1 (PAI-1) inhibitor compound according to claim 2 in an amount effective to increase HDL.

16. A method of decreasing circulating very low density lipoprotein (VLDL) in a subject, comprising administering to said subject a plasminogen activator inhibitor-1 (PAI-1) inhibitor compound according to claim 2 in an amount effective to decrease VLDL.

17. A method of modulating cholesterol and/or lipid uptake comprising the step of administering a PAI-1 inhibitor compound according to claim 2 in an amount effective to modulate cholesterol and/or lipid uptake.

18. A method of modulating cholesterol and/or lipid clearance comprising the step of administering a plasminogen activator inhibitor-1 (PAI-1) inhibitor compound according to claim 2 in an amount effective to inhibit very low density lipoprotein (VLDL) or apolipoprotein E (ApoE) or apolipoprotein A (ApoA) binding to VLDL-R and modulate cholesterol and/or lipid clearance.

19. A method of modulating cholesterol and/or lipid clearance comprising the step of administering a plasminogen activator inhibitor-1 (PAI-1) inhibitor compound according to claim 2 in an amount effective to affect HDL or apolipoprotein E (ApoE) or apolipoprotein A (ApoA) binding to an ApoA receptor and modulate cholesterol and/or lipid clearance.

20. A composition comprising the compound according to claim 2 and a pharmaceutically acceptable carrier.

Assignees

• Univ Michigan Regents
• Eastern Michigan Univ

Inventors

• Lawrence Daniel A
• Emal Cory
• Cale Jacqueline
• Su Enming Joe
• Warnock Mark
• Li Shih-Hon
• Cupp Jeanne Ann

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07C235/68

  having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom and to a carbon atom of a six-membered aromatic ring wherein at least one ortho-hydrogen atom has been replaced · CPC title