Novel bis-arylsulfonamides and aryl sulfonimides as inactivators of plasminogen activator inhibitor-1 (PAI-1)

Abstract

Inactivators of plasminogen activator inhibitor-1 (PAI-1) have been identified as possible treatments for a range of conditions, including atherosclerosis, venous thrombosis, and obesity. We describe the synthesis and inhibitory activity of a novel series of compounds based on bis-arylsulfonamide and aryl sulfonimide motifs that show potent and specific activity towards PAI-1. Inhibitors containing short linking units between the sulfonyl moieties and a 3,4-dihydroxy aryl substitution pattern showed the most potent inhibitory activity, and retained high specificity for PAI-1 over the structurally-related serpin anti-thrombin III (ATIII). Keywords PAI-1 inhibitors; bis-arylsulfonamide; aryl sulfonimidePlasminogen activator inhibitor-1 (PAI-1) is member of the serpin superfamily of protease inhibitors and is the primary inhibitor of urokinase type plasminogen activator (uPA) and tissue type plasminogen activator (tPA). 1 At normal physiologic levels PAI-1 plays a significant role in multiple processes, including fibrinolysis, angiogenesis, cell migration, and wound healing. [2][3][4][5][6] Pathologic levels of PAI-1 have been connected with obesity and metabolic syndrome, tumor metastasis, and vascular diseases such as venous thrombosis and atherosclerosis, making it an attractive pharmacological target. 7-13 However, PAI-1 has proven to be a challenging target for drug design as it is present in multiple conformational forms and has a flexible reactive center loop. Despite the challenges inherent in the development of small-molecule PAI-1 inactivators, several have been reported recently, although each has drawbacks that have impeded further progress in their development. [14][15][16][17][18][19][20][21][22] The most studied of these inhibitors, tiplaxtinin, 3,19,[23][24][25][26] Supplementary material containing synthetic details, spectroscopic characterization of novel compounds, and assay conditions for this paper is available to all readers.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptBioorg Med Chem Lett. Author manuscript; available in PMC 2011 February 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptHere we report the development of a novel class of PAI-1 inhibitors based on an aryl sulfonamide or aryl sulfonimide motif that shows up to 30-fold more potent inhibitory activity toward PAI-1 than that of tiplaxtinin. Based on insights gained from a screen for anti-PAI-1 activity of a library of structurally diverse compounds, 27 we developed a set of compounds designed to probe structural requi...

Small molecules inhibitors of plasminogen activator inhibitor-1 – An overview

“…In 2010, the same authors [94] synthesized new series of polyphenol analogs containing two polyphenolic moieties separated by bis-arylsulfonamide (50) or sulfonimide (51) linking units of variable length as substitutes for ester linkages (Scheme 23).…”

Effects of Altered Plasminogen Activator Inhibitor-1 Expression on Cardiovascular Disease

“…PAI-749 is another small molecule inhibitor of PAI-1 and neutralizes this protein utilizing dual mechanisms involving blocking the ability of the inhibitor to interact with plasminogen activators, uPA (IC 50 = 87 nM) and tPA (IC 50 = 150 nM), as well as rendering PAI-1 susceptible to plasmin mediated degradation [108]. More recently, novel bis-arylsulfonamide and arylsulfonamide derivatives have been developed that are 30X more potent than tiplaxtinin in regulating PAI-1 function as an antifibrinolytic protein [109]. Another class of active small molecules that target PAI-1 is polyphenolics.…”

Palladium‐Catalyzed ortho‐Benzoylation of Sulfonamides through C−H Activation: Expedient Synthesis of Cyclic N‐Sulfonyl Ketimines

“…5,6‐Dimethoxy‐3‐phenyl‐benzo[ d ]isothiazole‐1,1‐dioxide [27] (5 h) . Following the general procedure, the reaction of 3,4‐dimethoxy benzenesulfonamide with benzaldehyde gave 86 mg (57% yield) of 5 h as a white solid. M.P.…”