IP Library › Granted Patent US 12,390,427
Granted Patent B2
US 12,390,427 · App. 17/883,245 · Granted Aug 19, 2025

Plasminogen activator inhibitor-1 (PAI-1) inhibitor and method of use

Inventors: Daniel A. Lawrence (Ann Arbor, MI); Cory Emal (Ann Arbor, MI); Ashley Reinke (Appleton, WI); Shih-Hon Li (Canton, MI)
Assignees: EASTERN MICHIGAN UNIVERSITY; THE REGENTS OF THE UNIVERSITY OF MICHIGAN
A61K31/137
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Quick Facts
Patent No.
US 12,390,427
App. No.
17/883,245
Granted
Aug 19, 2025
Kind
B2
Abstract

Provided herein are plasminogen activator-1 (PAI-1) inhibitor compounds and uses thereof in the treatment of any disease or disorder associated with elevated PAI-1. The disclosure 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 (6)

1. A method of inhibiting plasminogen activator inhibitor-1 (PAI-1) comprising contacting PAI-1 with a compound which is

in an amount effective to inhibit PAI-1.

2. A method of treating fibrosis, comprising administering to a subject in need thereof a compound which is

or a pharmaceutically acceptable salt thereof, in an amount effective to treat fibrosis.

3. The method of claim 2 , wherein the fibrosis is pulmonary fibrosis, renal fibrosis, cardiac fibrosis, hepatic fibrosis, or scleroderma.

4. The method of claim 1 , wherein the compound is

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 12, 2023
From: EMAL, CORY
To: EASTERN MICHIGAN UNIVERSITY
Reel/Frame 063630/0077 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 12, 2023
From: LAWRENCE, DANIEL A.; REINKE, ASHLEY; LI, SHIH-HON
To: THE REGENTS OF THE UNIVERSITY OF MICHIGAN
Reel/Frame 063630/0088 →
Continuity (3)
Division 16631066
Provisional Application 62537513 · Jul 27, 2017
Related Publication 20220387356A1 · Dec 8, 2022
References Cited (194)
US 4618692A · Scheffler et al. · 1986 [cited by applicant]
US 4801749A · Kazmierczak et al. · 1989 [cited by applicant]
US 6528655B1 · N'Zemba et al. · 2003 [cited by applicant]
US 7351730B2 · Mayer et al. · 2008 [cited by applicant]
US 8759327B2 · Lawrence et al. · 2014 [cited by applicant]
US 9120744B2 · Lawrence et al. · 2015 [cited by applicant]
US 9718760B2 · Lawrence et al. · 2017 [cited by applicant]
US 10626112B2 · Kobayashi et al. · 2020 [cited by applicant]
US 10723785B2 · Eckelman et al. · 2020 [cited by applicant]
US 11426368B2 · Lawrence et al. · 2022 [cited by applicant]
US 20020052513A1 · Broadhurst et al. · 2002 [cited by applicant]
US 20050124664A1 · Sartori et al. · 2005 [cited by applicant]
US 20060058243A1 · Chen et al. · 2006 [cited by applicant]
US 20070155747A1 · Dasse et al. · 2007 [cited by applicant]
US 20100137194A1 · Lawrence et al. · 2010 [cited by applicant]
US 20150315178A1 · Lawrence et al. · 2015 [cited by applicant]
CN 101351495A · 2009 [cited by applicant]
EP 0555893A1 · 1993 [cited by applicant]
EP 1124157A2 · 2001 [cited by applicant]
EP 1719763A1 · 2006 [cited by applicant]
JP 1989066154A · 1989 [cited by applicant]
JP 1998287622A · 1998 [cited by applicant]
JP 2000171937A · 2000 [cited by applicant]
JP 2014523900A · 2014 [cited by applicant]
JP 7291119B2 · 2023 [cited by applicant]
WO WO9200968A1 · 1992 [cited by applicant]
WO WO9429267A1 · 1994 [cited by applicant]
WO WO9942435A2 · 1999 [cited by applicant]
WO WO03055843A1 · 2003 [cited by applicant]
WO WO2005000330A1 · 2005 [cited by applicant]
WO WO2007127505A2 · 2007 [cited by applicant]
WO WO2009017848A1 · 2009 [cited by applicant]
WO WO2014070983A1 · 2014 [cited by applicant]
WO WO2015115507A1 · 2015 [cited by applicant]
WO WO2019023526A1 · 2019 [cited by applicant]
Izuhara et al. Arteriosclerosis, Thrombosis and Vascular Biology 2008, 28 (4), 672-677. [cited by examiner]
Fortenberry Expert Opinion of Therapeutic Patents 2013, 23 (7), 801-815. [cited by examiner]
Ghosh et al. Journal of Cellular Physiology 2012, 227, 493-507. [cited by examiner]
Alessi et al., Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes. 46: 860-7 (1997). [cited by applicant]
Ashton et al., Nonpeptide angiotensin II antagonists derived from 4H-1,2,4-triazoles and 3H-imidazo[1,2-b][1,2,4] triazoles, J. Med. Chem., 36(5):591-609 (1993). [cited by applicant]
Berkenpas et al., Molecular evolution of plasminogen activator inhibitor-1 functional stability. EMBO J. 14: 2969-77 (1995). [cited by applicant]
Biemond, Thrombolysis and reocclusion in experimental jugular vein and coronary artery thrombosis. Effects of a plasminogen activator inhibitor type 1-neutralizing monoclonal antibody. Circulation. 91: 1175 (1995). [cited by applicant]
Boncoraglio et al., An effect of the PAI-1 4G/5G polymorphism on cholesterol levels may explain conflicting associatations with myocardial infarction and stroke. [cited by applicant]
Booth, Fibrinolysis and thrombosis. Baillieres Best. Pract. Res. Clin. Haematol. 12: 423-33 (1999). [cited by applicant]
Boucher et al., LRP: role in vascular wall integrity and protection from atherosclerosis. Science. 300: 329-32 (2003). [cited by applicant]
Bu, Receptor-associated protein: a specialized chaperone and antagonist for members of the LDL receptor gene family. Curr. Opin. Lipidol. 9: 149-55 (1998). [cited by applicant]
Butenas et al., Ultrasensitive fluorogenic substrates for serine proteases. Thromb. Haemost. 78: 1193-1201 (1997). [cited by applicant]
Cao et al., A specific role of integrin Mac-1 in accelerated macrophage efflux to the lymphatics. Blood. 106: 3234-41 (2005). [cited by applicant]
Cao et al., Endocytic receptor LRP together with tPA and PAI-1 coordinates Mac-1-dependent macrophage migration. EMBO J. 25: 1860-70 (2006). [cited by applicant]
Chen et al., 4G/5G promoter polymorphism of plasminogen activator inhibitor-1, lipid profiles, and ischemic stroke. [cited by applicant]
Chmielewska et al., Evidence for a rapid inhibitor to tissue plasminogen activator in plasma. Thromb. Res. 31: 427-36 (1983). [cited by applicant]
Choi et al., Generation of oxamic acid libraries: antimalarials and inhibitors of Plasmodium falciparum lactate dehydrogenase, J. Comb. Chem., 9(2):292-300 (2007). [cited by applicant]
Cigolini et al., Expression of plasminogen activator inhibitor-1 in human adipose tissue: a role for TNF-alpha? Atherosclerosis. 143: 81-90 (1999). [cited by applicant]
Clausen et al., Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 8: 265-77 (1999). [cited by applicant]
Colucci et al., Generation in plasma of a fast-acting inhibitor of plasminogen activator in response to endotoxin stimulation. J. Clin. Invest. 75: 818-24 (1985). [cited by applicant]
Crandall et al., Characterization and comparative evaluation of a structurally unique PAI-1 inhibitor exhibiting oral in-vivo efficacy. J. Thromb. Haemost. 2: 1422-1428 (2004). [cited by applicant]
Crandall et al., Modulation of adipose tissue development by pharmacological inhibition of PAI-1. Arterioscler. Thromb. Vasc. Biol. 26: 2209-15 (2006). [cited by applicant]
Crandall et al., Release of PAI-1 by human preadipocytes and adipocytes independent of insulin and IGF-1. Biochem. Biophys. Res. Commun. 279: 984-8 (2000). [cited by applicant]
Cuchel et al., Macrophage reverse cholesterol transport: key to the regression of atherosclerosis? Circulation. 113: 2548-55 (2006). [cited by applicant]
Czekay et al., Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins. J. Cell. Biol. 160: 781-91 (2003). [cited by applicant]
Daci et al., Mice lacking the plasminogen activator inhibitor 1 are protected from trabecular bone loss induced by estrogen deficiency. J. Bone Miner. Res. 15: 1510-6. (2000). [cited by applicant]
De Taeye et al., Bone marrow plasminogen activator inhibitor-1 influences the development of obesity. J. Biol. Chem. 281: 32796-805 (2006). [cited by applicant]
De Taeye et al., Plasminogen activator inhibitor-1: a common denominator in obesity, diabetes and cardiovascular disease. Curr. Opin. Pharmacol. 5: 149-54 (2005). [cited by applicant]
Deng et al., Is plasminogen activator inhibitor-1 the molecular switch that governs urokinase receptor-mediated cell adhesion and release? J. Cell. Biol. 134: 1563-71 (1996). [cited by applicant]
Dichtl et al., In vivo stimulation by vascular plasminogen activator inhibitor-1 production by very low-density lipoprotein involves transcription factor binding to a VLDL-responsive element. [cited by applicant]
Durand et al., Plasminogen activator inhibitor-I and tumour growth, invasion, and metastasis. Thromb. Haemost. 91: 438-49 (2004). [cited by applicant]
Ehrlich et al., Elucidation of structural requirements on plasminogen activator inhibitor 1 for binding to heparin. J. Biol. Chem. 267: 11606-11 (1992). [cited by applicant]
Eitzman et al., Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J. Clin. Invest. 97: 232-7 (1996). [cited by applicant]
Eitzman et al., Lack of plasminogen activator inhibitor-1 effect in a transgenic mouse model of metastatic melanoma. Blood. 87: 4718-22 (1996). [cited by applicant]
Elokdah et al., Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: design, synthesis, and preclinical characterization. J. Med. Chem. 47: 3491-4 (2004). [cited by applicant]
Erickson et al., Detection and partial characterization of an inhibitor of plasminogen activator in human platelets. J. Clin. Invest. 74: 1465-72 (1984). [cited by applicant]
European Patent Application No. 18837391, Extended European Search Report, dated Mar. 11, 2021. [cited by applicant]
Farkas et al., The recycling of apolipoprotein E in primary cultures of mouse hepatocytes. Evidence for a physiologic connection to high density lipoprotein metabolism. J. Biol. Chem. 278: 9412-7 (2003). [cited by applicant]
Fay et al., Brief report: complete deficiency of plasminogen-activator inhibitor type 1 due to a frame-shift mutation. N. Engl. J. Med. 327: 1729-33 (1992). [cited by applicant]
Fay et al., Platelets inhibit fibrinolysis in vitro by both plasminogen activator inhibitor-1-dependent and -independent mechanisms. Blood. 83: 351-6 (1994). [cited by applicant]
Gaitatzis et al., Novel insights into siderophore formation in myxobacteria. [cited by applicant]
Giltay et al., Visceral fat accumulation is an important determinant of PAI-1 levels in young, nonobese men and women: modulation by cross-sex hormone administration. Arterioscler. Thromb. Vasc. Biol. 18: 1716-22 (1998). [cited by applicant]
Gorlatova et al., Mechanism of inactivation of plasminogen activator inhibitor-1 by a small molecule inhibitor. J. Biol. Chem. 282: 9288-96 (2007). [cited by applicant]
Gottschling-Zeller et al., Troglitazone reduces plasminogen activator inhibitor-1 expression and secretion in cultured human adipocytes. Diabetologia. 43: 377-83 (2000). [cited by applicant]
Hagglof et al., The reactive-center loop of active PAI-1 is folded close to the protein core and can be partially inserted. J. Mol. Biol. 335: 823-32 (2004). [cited by applicant]
Hamsten et al., Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N. Engl. J. Med. 313: 1557-63 (1985). [cited by applicant]
Hasty et al., The recycling of apolipoprotein E in macrophages: influence of HDL and apolipoprotein A-I. Lipid Res. 46: 1433-9 (2005). [cited by applicant]
Heeren et al., Recycling of apoprotein E is associated with cholesterol efflux and high density lipoprotein internalization. J. Biol. Chem. 278: 14370-8 (2003). [cited by applicant]
Hekman et al., Bovine plasminogen activator inhibitor 1: specificity determinations and comparison of the active, latent, and guanidine-activated forms. Biochemistry. 27: 2911-8 (1988). [cited by applicant]
Hekman et al., Endothelial cells produce a latent inhibitor of plasminogen activators that can be activated by denaturants. J. Biol. Chem. 260: 11581-7 (1985). [cited by applicant]
Hennan et al., Evaluation of PAI-039 [{1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl} (oxo)acetic acid], a novel plasminogen activator inhibitor-1 inhibitor, in a canine model of coronary artery thrombosis. J. P… [cited by applicant]
Herz et al., LDL receptor-related protein internalizes and degrades uPA-PAI-1 complexes and is essential for embryo implantation. Cell. 71: 411-21 (1992). [cited by applicant]
Horn et al., Plasminogen activator inhibitor 1 contains a cryptic high affinity receptor binding site that is exposed upon complex formation with tissue-type plasminogen activator. Thromb. Haemost. 80: 822-8 (1998). [cited by applicant]
Huber et al., Implications of the three-dimensional structure of alpha 1-antitrypsin for structure and function of serpins. Biochemistry. 28: 8951-66 (1989). [cited by applicant]
Huber et al., Plasminogen activator inhibitor type-1 (part one): basic mechanisms, regulation, and role for thromboembolic disease. J. Thromb. Thrombolysis. 11: 183-93 (2001). [cited by applicant]
Huntington et al., Structure of a serpin-protease complex shows inhibition by deformation. Nature. 407: 923-6 (2000). [cited by applicant]
Huntington et al., The serpins: nature's molecular mousetraps. Sci. Prog. 84: 125-36 (2001). [cited by applicant]
Hussain et al., The mammalian low-density lipoprotein receptor family. Annu. Rev. Nutr. 19: 141-72 (1999). [cited by applicant]
Hynes et al., Hydroxylamine derivatives as potential inhibitors of nucleic acid synthesis, J. Med. Chem., 16(5):576-8 (1973). [cited by applicant]
International Application No. PCT/US2018/043998, International Search Report and Written Opinion, mailed Oct. 10, 2018. [cited by applicant]
Jensen et al., Inhibition of plasminogen activator inhibitor-1 binding to endocytosis receptors of the low-density-lipoprotein receptor family by a peptide isolated from a phage display library. [cited by applicant]
Jensen et al., The vitronectin binding area of plasminogen activator inhibitor-1, mapped by mutagenesis and protection against an inactivating organochemical ligand. FEBS Lett. 521: 91-4 (2002). [cited by applicant]
Kannel, Overview of hemostatic factors involved in atherosclerotic cardiovascular disease. Lipids. 40: 1215-20 (2005). [cited by applicant]
Kazi et al., Structure—activity relationships of synthetic analogs of (−)-epigallocatechin-3-gallate as proteasome inhibitors, Anticancer Research, 24:943-54 (2004). [cited by applicant]
Keijer et al., On the target specificity of plasminogen activator inhibitor 1: the role of heparin, vitronectin, and the reactive site. Blood. 78: 1254-61 (1991). [cited by applicant]
Kockx et al., Apolipoprotein A-I-stimulated apolipoprotein E secretion from human macrophages is independent of cholesterol efflux. J. Biol. Chem. 279: 25966-77 (2004). [cited by applicant]
Kohler et al., Plasminogen-activator inhibitor type 1 and coronary artery disease. N. Engl. J. Med. 342: 1792-1801 (2000). [cited by applicant]
Krieger et al., Scavenger receptor class B type I is a multiligand HDL receptor that influences diverse physiologic systems. J. Clin. Invest. 108: 793-7 (2001). [cited by applicant]
Krishnamurti et al., Plasminogen activator inhibitor: a regulator of ancrod-induced fibrin deposition in rabbits et al., Blood. 69: 798 (1987). [cited by applicant]
Lambers et al., Activation of human endothelial cell-type plasminogen activator inhibitor (PAI-1) by negatively charged phospholipids. J. Biol. Chem. 262: 17492-6 (1987). [cited by applicant]
Lawrence et al., Characterization of the binding of different conformational forms of plasminogen activator inhibitor-1 to vitronectin. Implications for the regulation of pericellular proteolysis. J. Biol. Chem. 272: 76… [cited by applicant]
Lawrence et al., Engineering plasminogen activator inhibitor 1 mutants with increased functional stability. Biochemistry. 33: 3643-8 (1994). [cited by applicant]
Lawrence et al., Inactivation of plasminogen activator inhibitor by oxidants. Biochemistry. 25: 6351-5 (1986). [cited by applicant]
Lawrence et al., Localization of vitronectin binding domain in plasminogen activator inhibitor-1. J. Biol. Chem. 269: 15223-8 (1994). [cited by applicant]
Lawrence et al., Molecular Basis of Thrombosis and Hemostasis, Marcel Dekker Inc., New York, 517-43 (1995). [cited by applicant]
Lawrence et al., Partitioning of serpin-proteinase reactions between stable inhibition and substrate cleavage is regulated by the rate of serpin reactive center loop insertion into beta-sheet A. J. Biol. Chem. 275: 5839… [cited by applicant]
Lawrence et al., Purification of active human plasminogen activator inhibitor 1 from [cited by applicant]
Lawrence et al., Serpin reactive center loop mobility is required for inhibitor function but not for enzyme recognition. J. Biol. Chem. 269: 27657-62 (1994). [cited by applicant]
Lawrence et al., Serpin-protease complexes are trapped as stable acyl-enzyme intermediates. J. Biol. Chem. 270: 25309-12 (1995). [cited by applicant]
Lawrence et al., Structure-function studies of the SERPIN plasminogen activator inhibitor type 1. Analysis of chimeric strained loop mutants. J. Biol. Chem. 265: 20293-301 (1990). [cited by applicant]
Le Lay et al., Regulation of ABCA1 expression and cholesterol efflux during adipose differentiation of 3T3-L1 cells. J. Lipid Res. 44: 1499-1507 (2003). [cited by applicant]
Levi, Inhibition of plasminogen activator inhibitor-1 activity results in promotion of endogenous thrombolysis and inhibition of thrombus extension in models of experimental thrombosis. Circulation. 85: 305-12 (1992). [cited by applicant]
Levin et al., Conversion of the active to latent plasminogen activator inhibitor from human endothelial cells. Blood. 70: 1090-8 (1987). [cited by applicant]
Liang et al., Plasminogen activator inhibitor-1 modulates adipocyte differentiation. Am. J. Physiol. Endocrinol. Metab. 290: E103-13 (2006). [cited by applicant]
Lijnen et al., On the role of plasminogen activator inhibitor-1 in adipose tissue development and insulin resistance in mice. J. Thromb. Haemost. 3: 1174-9 (2005). [cited by applicant]
Lindahl et al., Stability of plasminogen activator inhibitor 1 (PAI-1). Thromb. Haemost. 62: 748-51 (1989). [cited by applicant]
Liu et al., Highly purified scavenger receptor class B, type I reconstituted into phosphatidylcholine/cholesterol liposomes mediates high affinity high density lipoprotein binding and selective lipid uptake. J. Biol. Ch… [cited by applicant]
Lopes et al., PAI-1 polymorphisms modulate phenotypes associated with the metabolic syndrome in obese and diabetic Caucasian population. [cited by applicant]
Loskutoff et al., Detection of an unusually stable fibrinolytic inhibitor produced by bovine endothelial cells. Proc. Natl. Acad. Sci. USA. 80: 2956-60 (1983). [cited by applicant]
Loskutoff et al., The adipocyte and hemostatic balance in obesity: studies of PAI-1. Arterioscler. Thromb. Vasc. Biol. 18: 1-6 (1998). [cited by applicant]
Lundgren et al., Elaboration of type-1 plasminogen activator inhibitor from adipocytes. A potential pathogenetic link between obesity and cardiovascular disease. Circulation. 93: 106-10 (1996). [cited by applicant]
Lupu et al., Localization and production of plasminogen activator inhibitor-1 in human healthy and atherosclerotic arteries. Arterioscler. Thromb. 13: 1090-1100 (1993). [cited by applicant]
Ma et al., Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Diabetes. 53: 336-46 (2004). [cited by applicant]
Mavri et al., Impact of adipose tissue on plasma plasminogen activator inhibitor-1 in dieting obese women. Arterioscler. Thromb. Vasc. Biol. 19: 1582-7 (1999). [cited by applicant]
Minor et al., Plasminogen activator inhibitor type 1 promotes the self-association of vitronectin into complexes exhibiting altered incorporation into the extracellular matrix. J. Biol. Chem. 277: 10337-45 (2002). [cited by applicant]
Morange et al., Glucocorticoids and insulin promote plasminogen activator inhibitor 1 production by human adipose tissue. Diabetes. 48: 890-5 (1999). [cited by applicant]
Mottonen et al., Structural basis of latency in plasminogen activator inhibitor-1. Nature. 355: 270-3 (1992). [cited by applicant]
Naski et al., Kinetics of inactivation of alpha-thrombin by plasminogen activator inhibitor-1. Comparison of the effects of native and urea-treated forms of vitronectin. J. Biol. Chem. 268: 12367-72 (1993). [cited by applicant]
Nilsson et al., VLDL activation of plasminogen activator inhibitor-1 (PAI-1) expression: Involvement of the VLDL receptor. [cited by applicant]
Nordt, Differential regulation by troglitazone of plasminogen activator inhibitor type 1 in human hepatic and vascular cells. J. Clin. Endocrin. Metabol. 85: 1563-8 (2000). [cited by applicant]
Ny et al., Cloning and sequence of a cDNA coding for the human beta-migrating endothelial-cell-type plasminogen activator inhibitor. Proc. Natl. Acad. Sci. USA. 83: 6776-80 (1986). [cited by applicant]
Ohashi et al., Reverse cholesterol transport and cholesterol efflux in atherosclerosis. QJM. 98: 845-56 (2005). [cited by applicant]
Petyunin et al., Amides and hydrazides of oxalic acid. IV. Hydrazides of N-substituted oxamic acids, Zhurnal Obshchei Khimii, 34(1):28-32 (1964). CAPLUS Accession No. 1964:60623. [cited by applicant]
Podor et al., Incorporation of vitronectin into fibrin clots. Evidence for a binding interaction between vitronectin and gamma A/gamma' fibrinogen. J. Biol. Chem. 277: 7520-8 (2002). [cited by applicant]
Podor et al., New insights into the size and stoichiometry of the plasminogen activator inhibitor type-1.vitronectin complex. J. Biol. Chem. 275: 25402-10 (2000). [cited by applicant]
Podor et al., Type 1 plasminogen activator inhibitor binds to fibrin via vitronectin. J. Biol. Chem. 275: 19788-94 (2000). [cited by applicant]
Pubchem AKOS005831248—Compound Summary, pp. 1-3 (Jun. 18, 2007). [cited by applicant]
Pubmed Compound Summary for CID 62533622, ‘Roxusqsrdixgtl-Uhfffaoysa-N’, US National Library of Medicine, Oct. 22, 2012, pp. 1-10 (p3). [cited by applicant]
Reilly, Both circulating and clot-bound plasminogen activator inhibitor-1 inhibit endogenous fibrinolysis in the rat. Arterioscler. and Thromb.. 11: 1276 (1991). [cited by applicant]
Renckens et al., The role of plasminogen activator inhibitor type 1 in the inflammatory response to local tissue injury. J. Thromb. Haemost. 3: 1018-25 (2005). [cited by applicant]
Robbie et al., Inhibitors of fibrinolysis are elevated in atherosclerotic plaque. Arterioscler. Thromb. Vasc. Biol. 16: 539-45 (1996). [cited by applicant]
Rodenburg et al., Binding of urokinase-type plasminogen activator-plasminogen activator inhibitor-1 complex to the endocytosis receptors alpha2-macroglobulin receptor/low-density lipoprotein receptor-related protein and… [cited by applicant]
Rohlmann et al., Inducible inactivation of hepatic LRP gene by cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants. J. Clin. Invest. 101: 689-95 (1998). [cited by applicant]
Ross et al., Atherosclerosis—an inflammatory disease. N. Engl. J. Med. 340: 115-26 (1999). [cited by applicant]
Ruiz et al., The apoE isoform binding properties of the VLDL receptor reveal marked differences from LRP and the LDL receptor. J. Lipid Res. 46: 1721-31 (2005). [cited by applicant]
Sakamoto et al., TNF-alpha and insulin, alone and synergistically, induce plasminogen activator inhibitor-1 expression in adipocytes. Am. J. Physiol. 276: C1391-7 (1999). [cited by applicant]
Samad et al., Distribution and regulation of plasminogen activator inhibitor-1 in murine adipose tissue in vivo. Induction by tumor necrosis factor-alpha and lipopolysaccharide. J. Clin. Invest. 97: 37-46 (1996). [cited by applicant]
Samad et al., Tissue distribution and regulation of plasminogen activator inhibitor-1 in obese mice. Mol. Med. 2: 568-82 (1996). Samad et al., Mol. Med. 2: 568-82 (1996). [cited by applicant]
Sawicki et al., A composite CMV-IE enhancer/beta-actin promoter is ubiquitously expressed in mouse cutaneous epithelium. Exp. Cell Res. 244: 367-9 (1998). [cited by applicant]
Schafer et al., Disruption of the plasminogen activator inhibitor 1 gene reduces the adiposity and improves the metabolic profile of genetically obese and diabetic ob/ob mice. FASEB J. 15: 1840-2 (2001). [cited by applicant]
Schneiderman et al., Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. Proc. Natl. Acad. Sci. USA. 89: 6998-7002 (1992). [cited by applicant]
Seiffert et al., Constitutive and regulated expression of vitronectin. Histol. Histopathol. 12: 787-97 (1997). [cited by applicant]
Seiffert et al., The cell adhesion domain in plasma vitronectin is cryptic. J. Biol. Chem. 272: 13705-10 (1997). [cited by applicant]
Sharp et al., The active conformation of plasminogen activator inhibitor 1, a target for drugs to control fibrinolysis and cell adhesion. Structure. 7: 111-8 (1999). [cited by applicant]
Sherman et al., Saturation mutagenesis of the plasminogen activator inhibitor-1 reactive center. J. Biol. Chem. 267: 7588-95 (1992). [cited by applicant]
Shimomura et al., Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nat. Med. 2: 800-803 (1996). [cited by applicant]
Smith et al., Pivotal role of PAI-1 in a murine model of hepatic vein thrombosis. Blood. 107: 132-4 (2006). [cited by applicant]
Sprengers et al., Plasminogen activator inhibitors. Blood. 69: 381-7 (1987). [cited by applicant]
Stefansson et al., Inhibition of angiogenesis in vivo by plasminogen activator inhibitor-1. J. Biol. Chem. 276: 8135-41 (2001). [cited by applicant]
Stefansson et al., Mutants of plasminogen activator inhibitor-1 designed to inhibit neutrophil elastase and cathepsin G are more effective in vivo than their endogenous inhibitors. J. Biol. Chem. 279: 29981-7 (2004). [cited by applicant]
Stefansson et al., Old dogs and new tricks: proteases, inhibitors, and cell migration. Sci. STKE. 2003: pe24 (2003). [cited by applicant]
Stefansson et al., Plasminogen activator inhibitor-1 and vitronectin promote the cellular clearance of thrombin by low density lipoprotein receptor-related proteins 1 and 2. J. Biol. Chem. 271: 8215-20 (1996). [cited by applicant]
Stefansson et al., Plasminogen activator inhibitor-1 contains a cryptic high affinity binding site for the low density lipoprotein receptor-related protein. J. Biol. Chem. 273: 6358-66 (1998). [cited by applicant]
Stefansson et al., Plasminogen activator inhibitor-1 in tumor growth, angiogenesis and vascular remodeling. Curr. Pharm. Des. 9: 1545-64 (2003). [cited by applicant]
Stefansson et al., The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin. Nature. 383: 441-3 (1996). [cited by applicant]
Stewart et al., Synthesis of 3-nitro-L-tyrosine peptides by means of active polyester intermediates derived from the nitrophenol side chain, Australian J. Chem. 3293:661-7 (1979). [cited by applicant]
STN Registry Database (accessed Aug. 8, 2016). [cited by applicant]
Strandberg et al., The oxidative inactivation of plasminogen activator inhibitor type 1 results from a conformational change in the molecule and does not require the involvement of the P1' methionine. J. Biol. Chem. 266… [cited by applicant]
Suganami et al., A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler. Thromb. Vasc. Biol. 25: 2062-8 (2005). [cited by applicant]
Supplemental Partial European Search Report, European application No. 13850232, mailed Jul. 6, 2016. [cited by applicant]
Takahashi et al., Purification and ATPase activity of human ABCA1. J. Biol. Chem. 281: 10760-8 (2006). [cited by applicant]
Takahashi et al., The very low density lipoprotein (VLDL) receptor—a peripheral lipoprotein receptor for remnant lipoproteins into fatty acid active tissues. Mol. Cell. Biochem. 248: 121-7 (2003). [cited by applicant]
Tomasini et al., Vitronectin. Prog. Hemost. Thromb. 10: 269-305 (1991). [cited by applicant]
Vague et al., Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level, and relative body weight in normal and obese subjects. Metabolism. 35: 250-3 (1986). [cited by applicant]
Van Eck et al., Role of the macrophage very-low-density lipoprotein receptor in atherosclerotic lesion development. Artherosclerosis. 183: 230-7 (2005). [cited by applicant]
Van Mourik et al., Purification of an inhibitor of plasminogen activator (antiactivator) synthesized by endothelial cells. J. Biol. Chem. 259: 14914-21 (1984). [cited by applicant]
Vassiliou et al., A novel efflux-recapture process underlies the mechanism of high-density lipoprotein cholesteryl ester-selective uptake mediated by the low-density lipoprotein receptor-related protein. Arterioscler. T… [cited by applicant]
Vaughan et al., Studies of recombinant plasminogen activator inhibitor-1 in rabbits. Pharmacokinetics and evidence for reactivation of latent plasminogen activator inhibitor-1 in vivo. Circ. Res. 67: 1281-6 (1990). [cited by applicant]
Vaughan, PAI-1 and atherothrombosis. J. Thromb. Haemost. 3: 1879-83 (2005). [cited by applicant]
Vezina et al., Apolipoprotein distribution in human lipoproteins separated by polyacrylamide gradient gel electrophoresis. J. Lipid Res. 29: 573-85 (1988). [cited by applicant]
Webb et al., Plasminogen activator inhibitor 1 functions as a urokinase response modifier at the level of cell signaling and thereby promotes MCF-7 cell growth. J. Cell. Biol. 152: 741-52 (2001). [cited by applicant]
Weisberg et al., Pharmacological inhibition and genetic deficiency of plasminogen activator inhibitor-1 attenuates angiotensin Il/salt-induced aortic remodeling. Arterioscler. Thromb. Vasc. Biol. 25: 365-71 (2005). [cited by applicant]
Weiss et al., Neutrophils degrade subendothelial matrices in the presence of alpha-1-proteinase inhibitor. Cooperative use of lysosomal proteinases and oxygen metabolites. J. Clin. Invest. 73: 1297-1303 (1984). [cited by applicant]
Wilczynska et al., The inhibition mechanism of serpins. Evidence that the mobile reactive center loop is cleaved in the native protease-inhibitor complex. J. Biol. Chem. 270: 29652-5 (1995). [cited by applicant]
Xu et al., Apolipoproteins of HDL can directly mediate binding to the scavenger receptor SR-BI, an HDL receptor that mediates selective lipid uptake. J. Lipid Res. 38: 1289-98 (1997). [cited by applicant]
Xu et al., Conservation of critical functional domains in murine plasminogen activator inhibitor-1. J. Biol. Chem. 279: 17914-20 (2004). [cited by applicant]
Yepes et al., Plasminogen Activator Inhibitor-1, Hemostasis and Thrombosis: Basic Principles and Clinical Practice, Lippincott Williams & Wilkins, 365-80 (2006). [cited by applicant]
Zannis et al., Role of apoA-I, ABCA1, Lcat, and SR-BI in the biogenesis of Hdl. J. Mol. Med. 84: 276-94 (2006). [cited by applicant]
Zhou et al., How vitronectin binds PAI-1 to modulate fibrinolysis and cell migration. Nat. Struct. Biol. 10: 541-4 (2003). [cited by applicant]