Evaluation of PAI-039 [{1-Benzyl-5-[4-(trifluoromethoxy)phenyl]-1<i>H</i>-indol-3-yl}(oxo)acetic Acid], a Novel Plasminogen Activator Inhibitor-1 Inhibitor, in a Canine Model of Coronary Artery Thrombosis

Hennan, James K.; Elokdah, Hassan; Leal, Mauricio; Ji, Allena J.; Friedrichs, Gregory S.; Morgan, Gwen A.; Swillo, Robert E.; Antrilli, Thomas M.; Hreha, Amy; Crandall, David L.

doi:10.1124/jpet.105.084129

Cited by 37 publications

(21 citation statements)

References 31 publications

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“…Recently, an orally active small molecule antagonist of PAI-1 (PAI-039) was shown to inhibit plasma PAI-1 activity and accelerate fibrinolysis of coronary artery thrombosis in dogs [Hennan et al, 2005] and provide protection against angiotensin II-induced aortic remodeling in mice [Weisberg et al, 2005]. These studies offer the much-awaited proof-of-concept for PAI-1 inhibitors in treating cardiovascular complications, thereby endorsing the concept of PAI-1 inhibitors to treat secondary complications of obesity.…”

Section: Discussionmentioning

confidence: 96%

Regulation of PAI‐1 gene expression during adipogenesis

Venugopal¹,

Hanashiro²,

Nagamine³

2007

J of Cellular Biochemistry

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Obesity is characterized by elevated levels of circulating plasminogen activator inhibitor-1 (PAI-1), which contribute towards the development of secondary disorders such as type 2 diabetes mellitus and cardiovascular complications. This increase in plasma PAI-1 levels is attributed to an increase in PAI-1 derived from adipose tissue. This study shows that adipose tissue evolved into a major PAI-1 producing organ by gaining capacity during adipocyte differentiation to respond to inducers of PAI-1 transcription. This is mediated by a decrease in E2F1 protein levels, an increase in pRB levels and a decrease in pRB phosphorylation, all leading to a decrease in levels of free E2F, a known transcriptional repressor of PAI-1. Depletion of E2F1-3 was sufficient for inducers such as insulin to potently induce PAI-1 gene expression in pre-adipocytes. Conversely, forced release of pRB-bound endogenous E2F using cell-penetrating peptides can suppress PAI-1 gene expression in adipocytes. This study describes the novel paradigm of cellular differentiation-associated increase in PAI-1 gene expression which is mediated by a decrease in repressor activity, and describes a way of desensitising terminally differentiated cells to PAI-1 inducing agents by restoring endogenous repressor activity.

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Section: Discussionmentioning

confidence: 96%

Regulation of PAI‐1 gene expression during adipogenesis

Venugopal¹,

Hanashiro²,

Nagamine³

2007

J of Cellular Biochemistry

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“…Hemostasis and the effects of PAI-1 gene inactivation have also been studied in PAI-1-deficient mice, with neither spontaneous bleeding nor delayed rebleeding evident (34). In addition, PAI-1 inhibitors have been evaluated in preclinical models of coronary occlusion and shown to exert an antithrombotic effect without altering homeostasis (35). Furthermore, in vitro studies demonstrated that PAZ-417 does not inhibit tPA-initiated lysis of clots formed with either reptilase or thrombin, further showing that clot dissolution is unperturbed.…”

Section: Discussionmentioning

confidence: 99%

Enhanced clearance of Aβ in brain by sustaining the plasmin proteolysis cascade

Js¹,

Ta²,

Martone³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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131

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The amyloid hypothesis states that a variety of neurotoxic ␤-amyloid (A␤) species contribute to the pathogenesis of Alzheimer's disease. Accordingly, a key determinant of disease onset and progression is the appropriate balance between A␤ production and clearance. Enzymes responsible for the degradation of A␤ are not well understood, and, thus far, it has not been possible to enhance A␤ catabolism by pharmacological manipulation. We provide evidence that A␤ catabolism is increased after inhibition of plasminogen activator inhibitor-1 (PAI-1) and may constitute a viable therapeutic approach for lowering brain A␤ levels. PAI-1 inhibits the activity of tissue plasminogen activator (tPA), an enzyme that cleaves plasminogen to generate plasmin, a protease that degrades A␤ oligomers and monomers. Because tPA, plasminogen and PAI-1 are expressed in the brain, we tested the hypothesis that inhibitors of PAI-1 will enhance the proteolytic clearance of brain A␤. Our data demonstrate that PAI-1 inhibitors augment the activity of tPA and plasmin in hippocampus, significantly lower plasma and brain A␤ levels, restore long-term potentiation deficits in hippocampal slices from transgenic A␤-producing mice, and reverse cognitive deficits in these mice.Alzheimer ͉ plasminogen activator inhibitor ͉ tissue plasminogen activator A lzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of intracellular neuronal tangles and extracellular parenchymal and vascular amyloid deposits containing ␤-amyloid peptide (A␤). A␤ is a 39-to 42-aa peptide derived from the proteolytic processing of the amyloid precursor protein (APP) (1). The ''amyloid hypothesis'' of AD postulates a central causal role for A␤ in AD pathogenesis and is supported by genetic and physiological evidence. All known early onset familial AD mutations result in enhanced levels of cytotoxic A␤ species, amyloid plaque deposition, and dementia. Furthermore, A␤ peptide is reported to be neurotoxic and synaptotoxic in vitro and in vivo, inhibiting long-term potentiation (LTP), a physiological correlate of memory (2). Based on these observations, a number of strategies to reduce brain A␤ levels are being pursued as therapeutic approaches to treat AD (3, 4).If the amyloid hypothesis of AD is correct and A␤ levels are pivotal to disease etiology, then the balance between A␤ production and catabolism is likely to be a key determinant of disease progression. It has been suggested that insufficient clearance of A␤ may account for elevated A␤ levels in the brain and the accumulation of pathogenic amyloid deposits in sporadic AD (5). A number of proteases have been implicated in the proteolytic clearance of A␤ from the CNS, including neprilysin, insulin-degrading enzyme, endothelin converting enzyme, and plasmin (3, 6-8). The relative contribution of these enzymes to A␤ catabolism remains unclear, but each protease may play a significant role in the degradation and clearance of A␤, resulting in a slowing of A␤ accumulation and aggregation and u...

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“…19 In addition, PAI-1 synthesis is stimulated by a variety of other factors, including cytokines, lipids, and growth factors, and its production by and action on the vasculature can directly impact the etiology of atherosclerosis. 20 Because PAI-039 is an orally active direct inhibitor of PAI-1 that exhibits efficacy in models of acute thrombosis and accelerated atherosclerosis, 13,21,22 we decided to evaluate its effects on adipose tissue development and diet-induced obesity. PAI-039 dose-dependently reduced both basal and glucose-stimulated active PAI-1 antigen in human preadipocytes without affecting PAI-1 gene expression, indicating that the inhibition of PAI-1 was through direct interaction with the target protein.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Adipose Tissue Development by Pharmacological Inhibition of PAI-1

Crandall

Quinet

Ayachi

et al. 2006

ATVB

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Objective-The effect of a novel small molecule plasminogen activator inhibitor (PAI-1) inhibitor on adipose tissue physiology was investigated. Methods and Results-In human preadipocyte cultures, PAI-039 inhibited both basal and glucose-stimulated increases in active PAI-1 antigen, yet had no effect on PAI-1 mRNA, suggesting a direct inactivation of PAI-1. Differentiation of human preadipocytes to adipocytes was associated with leptin synthesis, which was significantly reduced in the presence of PAI-039, together with an atypical adipocyte morphology characterized by a reduction in the size and number of lipid containing vesicles. In a model of diet-induced obesity, pair-fed C57 Bl/6 mice administered PAI-039 in a high-fat diet exhibited a dose-dependent reduction in body weight, epididymal adipose tissue weight, adipocyte volume, and circulating plasma active PAI-1. Plasma glucose, triglycerides, and leptin were also significantly reduced in drug-treated mice, and concentrations of PAI-039 associated with these physiological effects were near the in vitro IC 50 for the inhibition of PAI-1. Conclusions-Our results indicate that a small molecule inactivator of PAI-1 can neutralize glucose-stimulated increases in PAI-1in human preadipocyte cultures, reduce adipocyte differentiation, and prevent the development of diet-induced obesity. These data suggest the pharmacological inhibition of PAI-1 could be beneficial in diseases associated with expansion of adipose tissue mass. Key Words: adipocyte Ⅲ diabetes Ⅲ obesity Ⅲ PAI-1 T ype 2 diabetes accounts for Ͼ90% of diabetes globally and continues to increase at epidemic proportions. 1 Cardiovascular morbidity is a major burden in patients with type 2 diabetes, and their risk of death from cardiovascular disease is increased significantly over nondiabetic subjects. 2 Aggressive treatment of both diabetes and cardiovascular disease in this population through a combination of diet, exercise, and pharmacological therapy has recently been reported to result in a 20% reduction in cardiovascular events, 3 whereas treatment of hyperglycemia alone produces less benefit. 4 Taken together, a significant number of diabetics continue to exhibit vascular disease that is refractory to current therapy. See page 2183Plasminogen activator inhibitor-1 (PAI-1) is the principal inhibitor of both tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), 5 and is physiologically involved in both thrombosis and atherosclerosis. 6 PAI-1 is found in the circulation of healthy individuals at low concentrations, and although it has a potential regulatory role in tumorigenesis, inflammation, and thrombosis, 7 PAI-1 is both elevated in the plasma of type 2 diabetic patients and is an important predictor of the onset of the disease. 8 The discovery that PAI-1 is synthesized by adipose tissue suggested that it represents a possible causal link between obesity and the increased atherothrombosis observed in diabetics. This hypothesis is further supported by additional studies establi...

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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

Cited by 37 publications

References 31 publications

Regulation of PAI‐1 gene expression during adipogenesis

Regulation of PAI‐1 gene expression during adipogenesis

Enhanced clearance of Aβ in brain by sustaining the plasmin proteolysis cascade

Modulation of Adipose Tissue Development by Pharmacological Inhibition of PAI-1

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