US2017291893A1PendingUtilityA1
Plasminogen activator inhibitor-1 inhibitors and methods of use thereof
Est. expiryOct 31, 2032(~6.3 yrs left)· nominal 20-yr term from priority
C07D 209/34C07D 207/48C07C 235/34C07C 235/80C07D 271/113C07C 311/48C07D 249/08C07C 243/26C07C 275/64C07C 311/37C07D 277/34C07C 237/20C07C 323/60C07D 209/08C07C 311/29C07C 69/94C07C 271/16C07D 417/10C07D 417/04C07D 261/18C07D 213/42C07C 311/49C07C 311/17C07C 259/06C07C 251/76C07C 235/46C07C 233/56C07C 69/84C07C 233/13
48
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Claims
Abstract
The invention relates to plasminogen activator- 1 (PAI- 1 ) inhibitor compounds and uses thereof in the treatment of any disease or disorder associated with elevated PAI- 1 . The invention includes, but is not limited to, the use of such compounds to prevent or reduce thrombosis and fibrosis, to promote thrombolysis, and to modulate lipid metabolism and treat diseases or disorders associated with elevated PAI- 1 , cholesterol, or lipid levels.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of formula I or a salt, ester, or prodrug thereof:
wherein:
R 1 is selected from the group consisting of C 1 to C 12 alkyl, -L 1 -C 3 -C 6 cycloalkyl, -L 2 -C 2 -C 6 heterocycloalkyl, benzyl, -L 3 -aryl, and -L 4 -heteroaryl;
R 2 is selected from the group consisting of -L 5 -C(═O)R 3 , -L 6 -R 4 , and NHR 5 ;
R 3 is selected from the group consisting of OR 6 , NR 7 R 8 , and NHNHR 9 ;
R 5 is selected from the group consisting of OR 10 , C 1 to C 12 alkyl, -L 7 -C 3 -C 6 cycloalkyl, -L 8 -C 2 -C 6 heterocycloalkyl, benzyl, -L 9 -aryl, and -L 10 -heteroaryl;
R 8 is selected from the group consisting of OR 11 , N═R 12 R 13 , -L 11 R 14 , NHSO 2 R 15 , and NHR 16 ;
R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 17 are independently selected from the group consisting of H and C 1 to C 12 alkyl;
R 4 , R 14 , R 15 , R 16 are independently selected from the group consisting of -L 12 -C 3 -C 6 cycloalkyl, -L 13 -C 2 -C 6 heterocycloalkyl, benzyl, -L 14 -aryl, and -L 15 -heteroaryl; and
L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , L 11 , L 12 , L 13 , L 14 , and L 15 are independently selected from the group consisting of null, C 1 to C 12 alkylene, and C 1 to C 12 alkenylene.
2 . The compound of claim 1 having a formula selected from the group consisting of II, III, IV, and salts, esters, or prodrugs thereof:
3 . The compound of claim 1 having a formula selected from the group consisting of V, VI, VII, and salts, esters, or prodrugs thereof:
4 . The compound of claim 1 , wherein R 1 is selected from the group consisting of:
pentyl, and butyl.
5 . The compound of claim 1 , wherein R 4 is selected from the group consisting of:
6 . The compound of claim 1 , wherein R 5 is OH.
7 . The compound of claim 1 , wherein R 8 is selected from the group consisting of:
8 . The compound of claim 1 having a formula selected from the group consisting of C256, C259, C265, C267, C276, C277, C288, C309, C311, C280, C300, C313, C314, C320, C323, C326, C328, C334, C342, C240, C241, C246, C248, C251, C255, C260, C261, C262, C263, C264, C266, C268, C278, C281, C282, C287, C289, C295, C296, C297, C301, C304, C305, C307, C310, C322, C336, C339, C340, C341, C362, C279, C285, C286, C299, C306, C330, C344, C345, C346, C347, C348, C356, C357, C358, C359, C360, C361, C363, C364, C284, and salts, esters, or prodrugs thereof:
9 . A compound of formula VIII 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, C 1 to C 12 alkyl, 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;
R a is 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; and
m is 1, 2, 3, 4, 5, or 6;
with the proviso that at most two of X 1 , X 2 , X 3 , X 4 , and X 5 are OH; and excluding a compound of formula
10 . The compound of claim 9 , wherein at most three of X 1 , X 2 , X 3 , X 4 , and X 5 are H.
11 . The compound of claim 9 having a formula selected from the group consisting of C152, C155, C173, C189, C191, C197, C224, C292, C293, C294, and salts, esters, or prodrugs thereof:
12 . A compound of formula IX or a salt, ester, or prodrug thereof:
wherein R a is selected from the group consisting of aryl, heteroaryl, (CH 2 ) m -heteroaryl, and substituted derivatives thereof; and
m is 1, 2, 3, 4, 5, or 6.
13 . The compound of claim 12 , wherein R a is selected from the group consisting of:
wherein: W is C or N; and
R 1 and R 2 are independently selected from the group consisting of —H, —F, —Cl, —Br, —I, —CF 3 , C 1 to C 12 alkyl, and phenyl.
14 . The compound of claim 12 having a formula selected from the group consisting of C153, C162, C163, C165, C188, C195, and salts, esters, or prodrugs thereof:
15 . A compound having a formula selected from the group consisting of C157, C158, C182, C183, and salts, esters, or prodrugs thereof:
16 . A compound of formula X or a salt, ester, or prodrug thereof:
wherein
R a is C 1 to C 12 alkyl,
R b is selected from the group consisting of C 1 to C 12 alkyl, aryl, heteroaryl, (CH 2 ) m —R, and
or
R a and R b taken together with the N atom to which they are bonded form an optionally substituted 3-, 4-, 5-, 7-, or 8-membered heterocyclic ring;
m is 1, 2, 3, 4, 5, or 6;
n is 0, 1, 2, 3, 4, 5, or 6;
Y is selected from the group consisting of NH 2 and OH; and
R selected from the group consisting of
substituted phenyl and heteroaryl.
17 . The compound of claim 16 , wherein R a is selected from the group consisting of butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
18 . The compound of claim 16 , wherein R b is selected from the group consisting of butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, fluorophenyl, chlorophenyl, bromophenyl, iodophenyl, trifluoromethylphenyl, and dichlorohydroxyphenyl.
19 . The compound of claim 16 having a formula selected from the group consisting of C170, C171, C172, C175, C177, C179, C180, C186, C193, C205, and salts, esters, or prodrugs thereof:
20 . A compound of formula XI or a salt, ester, or prodrug thereof:
wherein
R b is selected from the group consisting of aryl, heteroaryl, (CH 2 ) m —R, and
m is 1, 2, 3, 4, 5, or 6;
n is 0, 1, 2, 3, 4, 5, or 6;
Y is selected from the group consisting of NH 2 and OH; and
R selected from the group consisting of
CO 2 H, phenyl, substituted phenyl and heteroaryl.
21 . The compound of claim 20 having a formula selected from the group consisting of C160, C187, C190, C198, C232, C233, C249, C270, C271, C272, C273, C274, C275, C303, and salts, esters, or prodrugs thereof:
22 . A compound of formula XII or a salt, ester, or prodrug thereof:
wherein
R b is selected from the group consisting of aryl, heteroaryl, (CH 2 ) m —R, and
m is 1, 2, 3, 4, 5, or 6;
n is 0, 1, 2, 3, 4, 5, or 6;
Y is selected from the group consisting of NH 2 and OH; and
R selected from the group consisting of
CO 2 H, phenyl, substituted phenyl and heteroaryl.
23 . The compound of claim 22 having a formula selected from the group consisting of C210 and salts, esters, or prodrugs thereof:
24 . A compound having a formula selected from the group consisting of C168, C176, C184, C185, C196, and salts, esters, or prodrugs thereof:
25 . A compound having a formula selected from the group consisting of C156, C161, C200, C204, C236, and salts, esters, or prodrugs thereof:
26 . A compound of formula XIII or a salt, ester, or prodrug thereof:
wherein
n is 0 or 1;
R a and R b are 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; and
m is 1, 2, 3, 4, 5, or 6.
27 . The compound of claim 26 , wherein R a and R b are independently selected from the group consisting of butyl, pentyl, cyclopropyl, phenyl, difluorophenyl, and hydroxyphenyl.
28 . The compound of claim 26 having a formula selected from the group consisting of C201, C208, C213, C216, C220, C221, C222, C223, and salts, esters, or prodrugs thereof:
29 . A compound of formula XIV or a salt, ester, or prodrug thereof:
wherein R is selected from the group consisting of phenyl and substituted biphenyl.
30 . The compound of claim 29 having a formula selected from the group consisting of C199, C207, and salts, esters, or prodrugs thereof:
31 . A compound of formula XV or a salt, ester, or prodrug thereof:
wherein:
V is selected from the group consisting of (CH 2 ) n , C 3 to C 8 cycloalkyl, (CH 2 ) n —C 3 -C 8 cycloalkyl-(CH 2 ) p , aryl, (CH 2 ) n -aryl-(CH 2 ) p , heteroaryl, (CH 2 ) n -heteroaryl-(CH 2 ) p ,
and substituted derivatives thereof;
n and p are independently 0, 1, 2, 3, 4, 5, or 6;
X 1 , X 2 , X 3 , X 4 , X 5 and X 6 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, C 1 to C 12 alkyl, 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 1 is selected from the group consisting of O, NH, NR a , S, and CH 2 ;
Y 2 is selected from the group consisting of O, NH, NR b , S, and CH 2 ;
R a and R b are 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, 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 , Z 2 , Z 3 , and Z 4 are independently selected from the group consisting of C, P—OH, S, and S═O.
32 . The compound of claim 31 having a formula XVI or a salt, ester, or prodrug thereof:
33 . The compound of claim 31 having a formula selected from the group consisting of C225, and salts, esters, or prodrugs thereof:
34 . A compound of formula XVII or a salt, ester, or prodrug thereof:
wherein:
X 1 , X 2 , X 3 , X 4 , X 5 and X 6 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, C 1 to C 12 alkyl, 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;
R b is selected from the group consisting of H, 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, 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 4 is selected from the group consisting of C, P—OH, S, and S═O.
35 . The compound of claim 34 having a formula XVIII or a salt, ester, or prodrug thereof:
36 . The compound of claim 34 , wherein X 1 and X 2 are independently selected from the group consisting of —OH and —OR.
37 . The compound of claim 34 having a formula selected from the group consisting of C227, C228, and salts, esters, or prodrugs thereof:
38 . A compound of formula XIX or a salt, ester, or prodrug thereof:
wherein:
X 3 , X 4 , and X 6 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 1 is selected from the group consisting of CHR a R b , OR a , NHR a , NR a R b , and SR a ;
R a and R b are 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, benzyl, aryl, (CH 2 ) m -aryl, heteroaryl, (CH 2 ) m -heteroaryl, —U, (CH 2 ) m —U, and substituted derivatives thereof, or R a and R b taken together with the N atom to which they are bonded form a 3- to 8-membered heterocyclic ring;
U is selected from the group consisting of —NR c R d , —NR c C(O)R e , —NR c C(O)OR e , —NR c C(O)NR f R e , —NR c C(O)SR e , —NR c P(O)(OH)R e , —NR c P(O)(OH)OR e , —NR c P(O)(OH)NR f R c , —NR c P(O)(OH)SR c , —NR c S(O)R c , —NR c S(O)OR c , —NR c S(O)NR f R e , —NR c S(O)SR e , —NR c S(O) 2 R e , —NR c S(O) 2 OR e , —NR c S(O) 2 NR f R e , —NR c S(O) 2 SR e , —OR f , —OC(O)R e , —OC(O)OR e , —OC(O)NR f R e , —OC(O)SR e , —OP(O)(OH)R c , —OP(O)(OH)OR c , —OP(O)(OH)NR d R c , —OP(O)(OH)SR c , —OS(O)R c , —OS(O)OR e , —OS(O)NR d R e , —OS(O)SR e , —OS(O) 2 R e , —OS(O) 2 OR e , —OS(O) 2 NR d R e , —OS(O) 2 SR, —C(O)OR c , —C(O)NR c R d , —C(O)SR c , and —C(O)R c ;
R c and R d are independently selected from the group consisting of H, C 1 to C 12 alkyl, C 1 to C 12 haloalkyl, 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, benzyl, aryl, (CH 2 ) m -aryl, heteroaryl, (CH 2 ) m -heteroaryl, and substituted derivatives thereof, or R c and R d taken together with the N atom to which they are bonded form a 3- to 8-membered heterocyclic ring;
R e , R f , and R g are independently selected from the group consisting of H, C 1 to C 12 alkyl, C 1 to C 12 haloalkyl, 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, 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 4 are independently selected from the group consisting of C, P—OH, S, and S═O.
39 . The compound of claim 38 having a formula selected from the group consisting of C229, and salts, esters, or prodrugs thereof:
40 . A composition comprising an isolated compound according to any one of Formulas I to XIX, C256, C259, C265, C267, C276, C277, C288, C309, C311, C280, C300, C313, C314, C320, C323, C326, C328, C334, C342, C240, C241, C246, C248, C251, C255, C260, C261, C262, C263, C264, C266, C268, C278, C281, C282, C287, C289, C295, C296, C297, C301, C304, C305, C307, C310, C322, C336, C339, C340, C341, C362, C279, C285, C286, C299, C306, C330, C344, C345, C346, C347, C348, C356, C357, C358, C359, C360, C361, C363, C364, C284, C152, C155, C173, C189, C191, C197, C224, C292, C293, C294, C153, C162, C163, C165, C188, C195, C157, C158, C182, C183, C170, C171, C172, C175, C177, C179, C180, C186, C193, C205, C160, C187, C190, C198, C232, C233, C249, C270, C271, C272, C273, C274, C275, C303, C210, C168, C176, C184, C185, C196, C156, C161, C200, C204, C236, C201, C208, C213, C216, C220, C221, C222, C223, C199, C207, C225, C227, C228, or C229, or a salt, ester, or prodrug thereof, wherein said compound is present in an amount effective to inhibit PAI- 1 .
41 . A composition comprising the compound according to any one of Formulas I to XIX, C256, C259, C265, C267, C276, C277, C288, C309, C311, C280, C300, C313, C314, C320, C323, C326, C328, C334, C342, C240, C241, C246, C248, C251, C255, C260, C261, C262, C263, C264, C266, C268, C278, C281, C282, C287, C289, C295, C296, C297, C301, C304, C305, C307, C310, C322, C336, C339, C340, C341, C362, C279, C285, C286, C299, C306, C330, C344, C345, C346, C347, C348, C356, C357, C358, C359, C360, C361, C363, C364, C284, C152, C155, C173, C189, C191, C197, C224, C292, C293, C294, C153, C162, C163, C165, C188, C195, C157, C158, C182, C183, C170, C171, C172, C175, C177, C179, C180, C186, C193, C205, C160, C187, C190, C198, C232, C233, C249, C270, C271, C272, C273, C274, C275, C303, C210, C168, C176, C184, C185, C196, C156, C161, C200, C204, C236, C201, C208, C213, C216, C220, C221, C222, C223, C199, C207, C225, C227, C228, or C229, or a salt, ester, or prodrug thereof and a pharmaceutically acceptable carrier.
42 . A method of treating or preventing a disease or disorder associated with an elevated level of PAI- 1 in a subject comprising administering an effective amount of a composition comprising the compound according to any one of Formulas I to XXIX, C256, C259, C265, C267, C276, C277, C288, C309, C311, C280, C300, C313, C314, C320, C323, C326, C328, C334, C342, C240, C241, C246, C248, C251, C255, C260, C261, C262, C263, C264, C266, C268, C278, C281, C282, C287, C289, C295, C296, C297, C301, C304, C305, C307, C310, C322, C336, C339, C340, C341, C362, C279, C285, C286, C299, C306, C330, C344, C345, C346, C347, C348, C356, C357, C358, C359, C360, C361, C363, C364, C284, C152, C155, C173, C189, C191, C197, C224, C292, C293, C294, C153, C162, C163, C165, C188, C195, C157, C158, C182, C183, C170, C171, C172, C175, C177, C179, C180, C186, C193, C205, C160, C187, C190, C198, C232, C233, C249, C270, C271, C272, C273, C274, C275, C303, C210, C168, C176, C184, C185, C196, C156, C161, C200, C204, C236, C201, C208, C213, C216, C220, C221, C222, C223, C199, C207, C225, C227, C228, or C229, or a salt, ester, or prodrug thereof and a pharmaceutically acceptable carrier to decrease the elevated level of PAI- 1 in the subject.
43 . The method of claim 42 , wherein the disease or disorder is cancer, septicemia, obesity, insulin resistance, a disease or disorder associated with dysregulation of lipid metabolism, a disease or disorder associated with an elevated level of VLDL or LDL, high cholesterol, a proliferative disease or disorder, fibrosis and fibrotic disease, coagulation homeostasis, cerebrovascular disease, microvascular disease, hypertension, dementia, atherosclerosis, osteoporosis, osteopenia, arthritis, asthma, heart failure, arrhythmia, angina, hormone insufficiency, Alzheimer's disease, hypertension, inflammation, sepsis, fibrinolytic disorder, stroke, dementia, coronary heart disease, myocardial infarction, stable and unstable angina, vascular disease, peripheral arterial disease, acute vascular syndrome, thrombosis, prothrombosis, deep vein thrombosis, pulmonary embolism, cerebrovascular disease, microvascular disease, hypertension, diabetes, hyperglycemia, hyperinsulinemia, malignant lesions, premalignant lesions, gastrointestinal malignancies, liposarcoma, epithelial tumor, and psoriasis, an extracellular matrix accumulation disorder, neoangiogenesis, myelofibrosis, fibrinolytic impairment, polycystic ovary syndrome, bone loss induced by estrogen deficiency, angiogenesis, neoangiogenesis, myelofibrosis, or fibrinolytic impairment.
44 . The method of claim 43 , wherein the disease or disorder involving thrombosis or prothrombosis is formation of atherosclerotic plaques, venous thrombosis, arterial thrombosis, myocardial ischemia, atrial fibrillation, deep vein thrombosis, a coagulation syndrome, pulmonary thrombosis, cerebral thrombosis, a thromboembolic complication of surgery, and peripheral arterial occlusion.
45 . The method of claim 43 , wherein the disease or disorder is fibrosis.
46 . The method of claim 43 , wherein the extracellular matrix accumulation disorder is renal fibrosis, chronic obstructive pulmonary disease, polycystic ovary syndrome, restenosis, renovascular disease, diabetic nephropathy, or organ transplant rejection.
47 . A method of modulating cholesterol, lipid clearance, and/or lipid uptake in a subject with an elevated level of PAI- 1 comprising administering an effective amount of a composition comprising the compound according to any one of Formulas Ito XXIX, C256, C259, C265, C267, C276, C277, C288, C309, C311, C280, C300, C313, C314, C320, C323, C326, C328, C334, C342, C240, C241, C246, C248, C251, C255, C260, C261, C262, C263, C264, C266, C268, C278, C281, C282, C287, C289, C295, C296, C297, C301, C304, C305, C307, C310, C322, C336, C339, C340, C341, C362, C279, C285, C286, C299, C306, C330, C344, C345, C346, C347, C348, C356, C357, C358, C359, C360, C361, C363, C364, C284, C152, C155, C173, C189, C191, C197, C224, C292, C293, C294, C153, C162, C163, C165, C188, C195, C157, C158, C182, C183, C170, C171, C172, C175, C177, C179, C180, C186, C193, C205, C160, C187, C190, C198, C232, C233, C249, C270, C271, C272, C273, C274, C275, C303, C210, C168, C176, C184, C185, C196, C156, C161, C200, C204, C236, C201, C208, C213, C216, C220, C221, C222, C223, C199, C207, C225, C227, C228, or C229, or a salt, ester, or prodrug thereof and a pharmaceutically acceptable carrier in an amount effective to decrease the elevated level of PAI and modulate cholesterol, lipid clearance, and/or lipid uptake in the subject.
48 . The method of claim 47 , wherein the composition increases circulating high density lipoprotein (HDL) and/or decreases circulating very low density lipoprotein (VLDL) in the subject.
49 . The method of claim 47 , wherein the composition inhibits apolipoprotein E (ApoE) or apolipoprotein A (ApoA) binding to VLDL-R.
50 . The method of claim 47 , wherein the composition affects HDL or apolipoprotein E (ApoE) or apolipoprotein A (ApoA) binding to an ApoA receptor.
51 . The method of claim 47 , wherein the composition decreases PAI- 1 binding to apolipoprotein E (ApoE).
52 . The method of claim 47 , wherein the composition decreases PAI- 1 binding to apolipoprotein A (ApoA).
53 . The method of claim 47 , wherein the composition decreases PAI- 1 binding to VLDL.
54 . The method of claim 47 , wherein the composition binds to PAI- 1 in the presence of vitronectin.
55 . The method of claim 47 , wherein the composition binds to PAI- 1 in the presence of urokinase type plasminogen activator (uPA).
56 . The method of any one of claims 42 - 55 wherein the subject is human.Join the waitlist — get patent alerts
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