Tiplasinin

Tiplasinin
Clinical data
Other names	Tiplaxtinin; PAI-039
ATC code	None;
Identifiers
	IUPAC name (1-benzyl-5-(4-(trifluoromethoxy)phenyl)-1H-indol-3-yl)oxoacetic acid;
CAS Number	393105-53-8;
PubChem CID	6450819;
ChemSpider	4953369;
UNII	L396QIB983;
KEGG	D06160;
Chemical and physical data
Formula	C24H16F3NO4
Molar mass	439.38 g/mol g·mol−1
3D model (JSmol)	Interactive image;
	SMILES c2ccccc2Cn(cc1C(=O)C(O)=O)c4c1cc(cc4)-c(cc3)ccc3OC(F)(F)F;

Tiplasinin (INN, USAN) or tiplaxtinin (PAI-039) is a drug which acts as an inhibitor of the serpin protein plasminogen activator inhibitor-1 (PAI-1), thereby increasing activity of the enzymes tissue plasminogen activator and urokinase, which are involved in the blood clotting cascade. Inhibition of PAI-1 can help to prevent damage to blood vessel walls that occurs as a consequence of chronic high blood pressure, as well as preventing the formation of blood clots that can lead to stroke and heart attack, and potentially also providing a novel treatment mechanism to slow the development of diabetes and obesity. Tiplasinin was unsuccessful in human clinical trials due to an unfavourable risk to benefit ratio and the need for tight dose control to avoid provoking bleeding disorders, however it is still widely used in scientific research and newer drugs sharing the same mechanism of action are likely to be developed for medical use in future.[1][2][3]

References

Elokdah H, Abou-Gharbia M, Hennan JK, McFarlane G, Mugford CP, Krishnamurthy G, Crandall DL. Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: design, synthesis, and preclinical characterization. J Med Chem. 2004 Jul 1;47(14):3491-4. Elokdah, H; Abou-Gharbia, M; Hennan, J. K; McFarlane, G; Mugford, C. P; Krishnamurthy, G; Crandall, D. L (2004). "Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: Design, synthesis, and preclinical characterization". Journal of Medicinal Chemistry. 47 (14): 3491–4. CiteSeerX 10.1.1.661.4972. doi:10.1021/jm049766q. PMID 15214776.
Hennan JK, Elokdah H, Leal M, Ji A, Friedrichs GS, Morgan GA, Swillo RE, Antrilli TM, Hreha A, Crandall DL. 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 Pharmacol Exp Ther. 2005 Aug;314(2):710-6. Hennan, J. K; Elokdah, H; Leal, M; Ji, A; Friedrichs, G. S; Morgan, G. A; Swillo, R. E; Antrilli, T. M; Hreha, A; Crandall, D. L (2005). "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". Journal of Pharmacology and Experimental Therapeutics. 314 (2): 710–6. doi:10.1124/jpet.105.084129. PMID 15860572.
Brown NJ. Therapeutic potential of plasminogen activator inhibitor-1 inhibitors. Ther Adv Cardiovasc Dis. 2010 Oct;4(5):315-24. Brown, N. J (2010). "Therapeutic potential of plasminogen activator inhibitor-1 inhibitors". Therapeutic Advances in Cardiovascular Disease. 4 (5): 315–24. doi:10.1177/1753944710379126. PMID 20660535.

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[1] Elokdah H, Abou-Gharbia M, Hennan JK, McFarlane G, Mugford CP, Krishnamurthy G, Crandall DL. Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: design, synthesis, and preclinical characterization. J Med Chem. 2004 Jul 1;47(14):3491-4. Elokdah, H; Abou-Gharbia, M; Hennan, J. K; McFarlane, G; Mugford, C. P; Krishnamurthy, G; Crandall, D. L (2004). "Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: Design, synthesis, and preclinical characterization". Journal of Medicinal Chemistry. 47 (14): 3491–4. CiteSeerX 10.1.1.661.4972. doi:10.1021/jm049766q. PMID 15214776.

[2] Hennan JK, Elokdah H, Leal M, Ji A, Friedrichs GS, Morgan GA, Swillo RE, Antrilli TM, Hreha A, Crandall DL. 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 Pharmacol Exp Ther. 2005 Aug;314(2):710-6. Hennan, J. K; Elokdah, H; Leal, M; Ji, A; Friedrichs, G. S; Morgan, G. A; Swillo, R. E; Antrilli, T. M; Hreha, A; Crandall, D. L (2005). "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". Journal of Pharmacology and Experimental Therapeutics. 314 (2): 710–6. doi:10.1124/jpet.105.084129. PMID 15860572.

[3] Brown NJ. Therapeutic potential of plasminogen activator inhibitor-1 inhibitors. Ther Adv Cardiovasc Dis. 2010 Oct;4(5):315-24. Brown, N. J (2010). "Therapeutic potential of plasminogen activator inhibitor-1 inhibitors". Therapeutic Advances in Cardiovascular Disease. 4 (5): 315–24. doi:10.1177/1753944710379126. PMID 20660535.