Treprostinil (diethanolamine salt)

Treprostinil is a derivative of prostaglandin I₂ and an agonist of PGI₂, PGD₂, and PGE₂ receptors IP₂, DP₂, and EP₂.^1,2 It binds selectively to IP₂, DP₂, and EP₂ over EP₁, EP₃, and EP₄ receptors with K_i values of 32, 4.4, 3.6, 212, 2,505, and 826 nM, respectively, in radioligand binding assays.² Treprostinil inhibits LPS-induced production of TNF-α, IL-1β, IL-6, and granulocyte macrophage colony-stimulating factor (GM-CSF) in isolated human alveolar macrophages when used at a concentration of 200 ng/ml.³ It also prevents LPS-induced nuclear translocation and activation of NF-κB in the same cells. Treprostinil relaxes isolated small pulmonary arteries and veins precontracted with the thromboxane A₂ (TP) receptor antagonist U-46619 , an effect that can be blocked by IP receptor antagonists in the arteries and reduced by IP receptor antagonists in the veins⁴. It reduces right ventricular systolic pressure, but not right ventricular hypertrophy, compared to hypoxic and sham control animals in a mouse model of chronic hypoxic pulmonary hypertension.⁵ Formulations containing treprostinil have been used in the treatment of primary pulmonary hypertension.

1.Syed, N.I., and Jones, R.L.Assessing the agonist profiles of the prostacyclin analogues treprostinil and naxaprostene, particularly their DP? activityProstaglandins Leukot. Essent. Fatty Acids9519-29(2015) 2.Clapp, L.H., and Gurung, R.The mechanistic basis of prostacyclin and its stable analogues in pulmonary arterial hypertension: Role of membrane versus nuclear receptorsProstaglandins Other Lipid Mediat.12056-71(2015) 3.Raychauduri, B., Malur, A., Bonfield, T.L., et al.The prostacyclin analogue treprostinil blocks NFκB nuclear translocation in human alveolar macrophagesThe Journal of Biological Chemisty277(36)33344-33348(2002) 4.Orie, N.N., Ledwozyw, A., Williams, D.J., et al.Differential actions of the prostacyclin analogues treprostinil and iloprost and the selexipag metabolite, MRE-269 (ACT-333679) in rat small pulmonary arteries and veinsProstaglandins Other Lipid Mediat.1061-7(2013) 5.Nikam, V.S., Schermuly, R.T., Dumitrascu, R., et al.Treprostinil inhibits the recruitment of bone marrow-derived circulating fibrocytes in chronic hypoxic pulmonary hypertensionEur. Respir. J.36(6)1302-1314(2010)