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

Patent metadata

Field	Value
Publication number	US-2016009748-A1
Application number	US-201514817690-A
Country	US
Kind code	A1
Filing date	Aug 4, 2015
Priority date	Apr 16, 2007
Publication date	Jan 14, 2016
Grant date	—

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

1 .- 39 . (canceled)

40 . A compound of formula CLXXV or a salt, ester, or prodrug thereof:

wherein:
W is C or N;
X 1 , X 2 , X 3 , X 4 , and X 5 are independently selected from the group consisting of —H, —OH, —OR, —F, —Cl, —Br, —I, —NO 2 , —NO, —N(R) 2 , —N(R) 3 + , —C(O)R, —C(O)OR, —CHO, —C(O)NH 2 , —C(O)SR, —CN, —S(O) 2 R, —SO 3 R, —SO 3 H, —SO 2 N(R) 2 , —S═O, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
R is selected from the group consisting of C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, CH 2 —C 3 -C 6 cycloalkyl, phenyl, tolyl, and benzyl;
Y is selected from the group consisting of O, NH, NR a , S, and CHR a ;
R a is independently selected from the group consisting of C 1 to C 12 alkyl, C 3 to C 6 cycloalkyl, (CH 2 ) m —C 3 -C 6 cycloalkyl, C 2 to C 6 heterocycloalkyl, (CH 2 ) m —C 2 -C 6 heterocycloalkyl, C 2 to C 6 heterocycloalkyl, (CH 2 ) m —C 2 -C 6 heterocycloalkyl, benzyl, aryl, (CH 2 ) m -aryl, heteroaryl, (CH 2 ) m -heteroaryl, and substituted derivatives thereof;
m is 1, 2, 3, 4, 5, or 6; and
Z 1 and Z 2 are independently selected from the group consisting of C, P—OH, S, and S═O.

41 . The compound of claim 40 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:

42 . The compound of claim 40 or a salt, ester, or prodrug thereof, having a formula CXLVI

wherein R a is C 3 to C 12 alkyl

43 . The compound of claim 40 or a salt, ester, or prodrug thereof, having a formula CXXXIII

wherein W, X 1 , X 2 , X 3 , X 4 , Y, Z 1 and Z 2 are as defined in claim 40 .

44 . 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 40 in an amount effective to increase HDL.

45 . 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 40 in an amount effective to decrease VLDL.

46 . The method of claim 44 , wherein the subject is human.

47 . The method of claim 44 , wherein the PAI-1 inhibitor decreases PAI-1 binding to apolipoprotein E (ApoE), apolipoprotein A (ApoA), and/or VLDL.

48 . (canceled)

49 . (canceled)

50 . The method of claim 44 , wherein the PAI-1 inhibitor binds to PAI-1 in the presence of vitronectin.

51 . The method of claim 44 , wherein the PAI-1 inhibitor binds to PAI-1 in the presence of urokinase type plasminogen activator (uPA).

52 . A method of modulating cholesterol and/or lipid uptake comprising the step of administering a PAI-1 inhibitor compound according to claim 40 in an amount effective to modulate cholesterol and/or lipid uptake.

53 . 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 40 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.

54 . 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 40 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.

55 . A composition comprising the compound according to claim 40 and a pharmaceutically acceptable carrier.

56 .- 63 . (canceled)

64 . The method of claim 45 , wherein the subject is human.

65 . The method of claim 45 , wherein the PAI-1 inhibitor decreases PAI-1 binding to apolipoprotein E (ApoE), apolipoprotein A (ApoA), and/or VLDL.

66 . The method of claim 45 , wherein the PAI-1 inhibitor binds to PAI-1 in the presence of vitronectin.

67 . The method of claim 45 , wherein the PAI-1 inhibitor binds to PAI-1 in the presence of urokinase type plasminogen activator (uPA).

Assignees

• Univ Michigan
• Eastern Michigan University

Inventors

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

Classifications

• A61P9/04

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · 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

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title