3-Mercaptopropionic acids as efficacious inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa)

Islam, Imadul; Bryant, Judi; May, Karen; Mohan, Raju; Shuanggui, Yuan; Kent, L; Morser, John; Zhao, Lei; Vergona, Ronald; White, Kathy; Adler, Marc; Whitlow, Marc; Buckman, Brad O.

doi:10.1016/j.bmcl.2006.11.078

Cited by 25 publications

(24 citation statements)

References 22 publications

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“…Thus, several site‐directed synthetic thrombin inhibitors (bivalirudin, argatroban and ximelagatran) have been developed, and their role in the treatment of coronary syndromes (32–34), stroke (35–47), systemic embolism (48,49) and the prevention of post‐surgery venous thromboembolism (50–55) is widely documented. Nevertheless, since hepato‐toxicity is observed in prolonged/acute administration of these synthetic compounds (56–58), the identification of non‐toxic natural occurring molecules (or derivatives thereof) as co‐drugs in the treatment of thrombin‐related pathologies is a stimulating test for current medicinal chemistry (59–70).…”

Section: Inhibition Of Serine Proteases Activity By Polyphenolsmentioning

confidence: 99%

Natural Occurring Polyphenols as Template for Drug Design. Focus on Serine Proteases

et al. 2009

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Several major physio-pathological processes, including cancer, inflammatory states and thrombosis, are all strongly dependent upon the fine regulation of proteolytic enzyme activities, and dramatic are the consequences of unbalanced equilibria between enzymes and their cognate inhibitors. In this perspective, the discovery of small-molecule ligands able to modulate catalytic activities has a massive therapeutic potential and is a stimulating goal. Numerous recent experimental evidences revealed that proteolytic enzymes can be opportunely targeted, reporting on small ligands capable of binding to these biological macromolecules with drug-like potencies, and primarily with comparable (or even higher) efficiency with respect to their endogenous binding partner. In particular, natural occurring polyphenols and their derivatives recently disclosed these intriguing abilities, making them promising templates for drug design and development. In this review, we compared the inhibitory capacities of a set of monomeric polyphenols toward serine proteases activity, and finally summarized the data with an emphasis on the derivation of a pharmacophore model.

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Section: Inhibition Of Serine Proteases Activity By Polyphenolsmentioning

confidence: 99%

Natural Occurring Polyphenols as Template for Drug Design. Focus on Serine Proteases

et al. 2009

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“…Nonetheless, TAFIa is sensitive to inhibition by chelating agents, by compounds that disrupt disulfide bridges, by small synthetic substrate analog inhibitors and by naturally occurring metallocarboxypeptidase inhibitors. 7,8 In vivo evidence for a role of TAFI in fibrinolysis is obtained in several animal models (eg, the efficiency of tPA-mediated thrombolysis is increased by inhibition of TAFIa through potato tuber carboxypeptidase inhibitor (PTCI). [9][10][11] However, the applicability of all these inhibitors is restricted given their lack in specificity and safety.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the profibrinolytic properties of an anti-TAFI monoclonal antibody in a mouse thromboembolism model

Vercauteren¹,

Emmerechts

Peeters³

et al. 2011

Blood

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The enhancement of fibrinolysis constitutes a promising approach to treat thrombotic diseases. Activated thrombin activatable fibrinolysis inhibitor (TAFIa) attenuates fibrinolysis and is an attractive target to develop profibrinolytic drugs. TAFI can be activated by thrombin, thrombin/thrombomodulin, or plasmin, but the in vivo physiologic TAFI activator(s) are unknown. Here, we generated and characterized MA-TCK26D6, a monoclonal antibody raised against human TAFI, and examined its profibrinolytic properties in vitro and in vivo. In vitro, MA-TCK26D6 showed a strong profibrinolytic effect caused by inhibition of the plasmin-mediated TAFI activation. In vivo, MA-TCK26D6 significantly decreased fibrin deposition in the lungs of thromboembolism-induced mice. Moreover, in the presence of MA-TCK26D6, plasmin-␣ 2 -antiplasmin complexes in plasma of thromboembolism-induced mice were significantly increased compared with a control antibody, indicative of an acceleration of fibrinolysis through MA-TCK26D6. In this study, we show that plasmin is an important TAFI activator that hampers in vitro clot lysis. Furthermore, this is the first report on an anti-TAFI monoclonal antibody that demonstrates a strong profibrinolytic effect in a mouse thromboembolism model. (Blood. 2011;117(17): 4615-4622)

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“…[178][179][180] These observations have prompted development of TAFIa-directed antibodies 181 and nanontibodies, 182 as well as small molecule TAFIa inhibitors. [183][184][185] A potential limitation of some such of fi brin and fi brinogen. 195 Because there is no need for plasmin generation, alfi meprase has the potential more, the action of alfi meprase is independent of the plasminogen content of the thrombus and alfi meprase is not inhibited by PAI-1.…”

Section: Tafia Inhibitorsmentioning

confidence: 99%

New Antithrombotic Drugs

Weitz

Eikelboom

Samama

2012

Chest

280

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3-Mercaptopropionic acids as efficacious inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa)

Cited by 25 publications

References 22 publications

Natural Occurring Polyphenols as Template for Drug Design. Focus on Serine Proteases

Natural Occurring Polyphenols as Template for Drug Design. Focus on Serine Proteases

Evaluation of the profibrinolytic properties of an anti-TAFI monoclonal antibody in a mouse thromboembolism model

New Antithrombotic Drugs

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