Design, synthesis and In vitro evaluation of potent, novel, small molecule inhibitors of plasminogen activator inhibitor-1

Folkes, Adrian; Brown, Suzanne; Canne, Lynne E.; Chan, Jocelyn; Engelhardt, Erin; Epshteyn, Sergey; Faint, Richard; Golec, J. M. C.; Hanel, Art; Kearney, Patrick C.; Leahy, James W.; Mac, Morrison B.; Matthews, David J.; Prisbylla, Michael P.; Sanderson, J.C.; Simon, Reyna J.; Tesfai, Zerom; Vicker, Nigel; Wang, Shouming; Webb, Robert R.; Charlton, Peter

doi:10.1016/s0960-894x(02)00078-1

Cited by 26 publications

(14 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the mechanistic role that PAI-1 plays in disease development is not clear and is likely to be complex, because PAI-1 can act through at least two distinctly different pathways, either by modulating fibrinolysis through the regulation of plasminogen activators, or by influencing tissue remodeling through the direct regulation of cell migration (31, 38 -41). The possibility that PAI-1 plays a direct role in a variety of diseases makes it an attractive target for small molecule drug development; however, the structural complexity of PAI-1 has made the identification and development of small molecule PAI-1-inactivating agents challenging (42)(43)(44)(45). Recently, a novel, orally active small molecule PAI-1 inhibitor, PAI-039, also called tiplaxtinin, has been described and examined in several animal models of disease where PAI-1 is thought to play a role (46 -52).…”

mentioning

confidence: 99%

Mechanism of Inactivation of Plasminogen Activator Inhibitor-1 by a Small Molecule Inhibitor

Gorlatova

Cale

Elokdah³

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

The inactivation of plasminogen activator inhibitor-1 (PAI-1) by the small molecule PAI-1 inhibitor PAI-039 (tiplaxtinin) has been investigated using enzymatic analysis, direct binding studies, site-directed mutagenesis, and molecular modeling studies. Previously PAI-039 has been shown to exhibit in vivo activity in various animal models, but the mechanism of inhibition is unknown. PAI-039 bound specifically to the active conformation of PAI-1 and exhibited reversible inactivation of PAI-1 in vitro. SDS-PAGE indicated that PAI-039 inactivated PAI-1 predominantly through induction of PAI-1 substrate behavior. Preincubation of PAI-1 with vitronectin, but not bovine serum albumin, blocked PAI-039 activity while analysis of the reciprocal experiment demonstrated that preincubation of PAI-1 with PAI-039 blocked the binding of PAI-1 to vitronectin. Together, these data suggest that the site of interaction of the drug on PAI-1 is inaccessible when PAI-1 is bound to vitronectin and may overlap with the PAI-1 vitronectin binding domain. This was confirmed by site-directed mutagenesis and molecular modeling studies, which suggest that the binding epitope for PAI-039 is localized adjacent to the previously identified interaction site for vitronectin. Thus, these studies provide a detailed characterization of the mechanism of inhibition of PAI-1 by PAI-039 against free, but not vitronectin-bound PAI-1, suggesting for the first time a novel pool of PAI-1 exists that is vulnerable to inhibition by inactivators that bind at the vitronectin binding site.

show abstract

mentioning

confidence: 99%

Mechanism of Inactivation of Plasminogen Activator Inhibitor-1 by a Small Molecule Inhibitor

Gorlatova

Cale

Elokdah³

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Folkes reported a series of tetramic acid derivatives containing an imide function at the 3-position and found that some of them show excellent potency against plasminogen activator inhibitor-1 Figure 1, B. 16 Zhu synthesized 3-[(α-hydroxy-substituted)benzylidene]pyrrolidine-2,4-diones and found them to exhibit good herbicidal activities Figure 1, C. 17 Recently, Raghunandan reported N-Substituted-3-acetyltetramic acid derivatives displaying antibacterial activities (Figure 1, D). 18 Additionally, some tenuazonic acid analogs such as, reutericyclin, cryptocin, β-cyclopiazonic acid, and melophlin A and B, derived from natural products, have been found and displayed a wide range of biological activities.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, characterization and biological activity of novel (5RS,6S)-5-sec-butyl-3-(1-substitutedamino)ethylidene -1H-pyrrolidine-2,4-diones

Wang¹,

Si²,

Li³

et al. 2010

Arkivoc

View full text Add to dashboard Cite

A series of novel tetramic acid derivatives, 5-sec-butyl-3-(1-substitutedamino)ethylidene-1H-pyrrolidine-2,4-diones 5a-y were synthesized by reaction with aryl amines or alkyl amines under reflux. Each title compound was formed as (5S,6S) and (5R,6S) C-5 epimers, and the structure of 5l was proved by X-ray diffraction analysis. Our preliminary bioassay results show the title compounds to exhibit some herbicidal activities and better antifungal activities than the leading compound tenuazonic acid at 100 mg L -1 in vitro, and the compound 5u displayed excellent herbicidal activity and antifungal activity.

show abstract

“…Type 2 diabetes is associated with heart failure, particularly heart failure with preserved systolic function potentially attributable in part to augmented cardiac Wbrosis (Donnan et al 2002;Gwilt et al 1985;Mizushige et al 2000;Perez et al 1992;Shimizu et al 1993Young et al 2002. Accordingly, increased PAI-1 expression may be a determinant of diastolic heart failure typically associated with diabetes, female sex, and hypertension, and agents that neutralize activity of PAI-1 (Folkes et al 2002) may attenuate the development of cardiac Wbrosis and its functional consequences as well as accelerating evolution of atherosclerotic plaques vulnerable to rupture (Sobel 1999). However, attenuation of PAI-1 expression or activity in the heart may be deleterious.…”

Section: Introductionmentioning

confidence: 99%

Deleterious effects of lack of cardiac PAI-1 after coronary occlusion in mice and their pathophysiologic determinants

Zaman

Fujii

Schneider

et al. 2007

Histochem Cell Biol

View full text Add to dashboard Cite

We sought to delineate mechanisms through which the lack of plasminogen activator inhibitor (PAI)-1 in the heart affects remodeling of the heart early after myocardial infarction (MI). MI was induced by coronary occlusion in 10-weeks old PAI-1 knockout (KO) and control mice. Three days after MI, systolic and diastolic function was assessed with high-resolution echocardiography, infarct size was determined biochemically and histologically and accumulation of acute inflammatory cells in zones of infarction was characterized by immunocytochemistry. PAI-1 KO mice exhibited markedly thickened diastolic left ventricular anterior walls (1.38 +/- 0.38 mm vs. 0.77 +/- 0.13 SD), more profound depression of global and regional cardiac function (19 vs. 22% fractional shortening), and greater evidence of diastolic dysfunction (average E wave amplitude = 568 vs. 675 mm/s) all of which were significant. Markedly greater extent of infarction was demonstrated biochemically and histologically in knockout mice compared with controls (76 vs. 29% of the left ventricle, P < 0.05) associated with striking hemorrhage and intense inflammation. Fibrosis normalized for infarct size was markedly reduced (0.006 vs. 0.022 microg hydroxyproline/mg dry weight). Thus, lack of PAI-1 in the heart exerted deleterious effects mediated, at least in part by increased inflammation and hemorrhage and attenuating of fibrosis.

show abstract

Design, synthesis and In vitro evaluation of potent, novel, small molecule inhibitors of plasminogen activator inhibitor-1

Cited by 26 publications

References 15 publications

Mechanism of Inactivation of Plasminogen Activator Inhibitor-1 by a Small Molecule Inhibitor

Mechanism of Inactivation of Plasminogen Activator Inhibitor-1 by a Small Molecule Inhibitor

Synthesis, characterization and biological activity of novel (5RS,6S)-5-sec-butyl-3-(1-substitutedamino)ethylidene -1H-pyrrolidine-2,4-diones

Deleterious effects of lack of cardiac PAI-1 after coronary occlusion in mice and their pathophysiologic determinants

Contact Info

Product

Resources

About