Thrombopoietin-receptor agonists

Small-molecule, nonpeptide thrombopoietin receptor agonists for oral use are being developed as a treatment for thrombocytopenia of various etiologies. 

VcF, and Vff and couplings have been measured by Reiter et al for a series of 2-amino-4-phenylthiazoles and analysed together with nuclear Overhauser effects from the point of view of conformational preferences of these compounds. This was a part of their studies on molecular features crucial to the activity of pyrimidine benzamide-based thrombopoietin receptor agonists. 

Thrombopoietin-receptor agonists have proved helpful in several clinical situations however, concerns of leu-kaemic transformation in patients with myelodysplastic syndrome, clinical significance of bone marrow fibrosis and thrombosis are areas for further study [144-146 ]. 

Homeida S, Ebdon C, Batty P, Jackson B, Kolade S, Bateman C, et al. New thrombopoietin receptor agonists for platelet disorders. Drugs Today 2012 48(4) 293-301. 

Basdano PA, Bussel JB. Thrombopoietin-receptor agonists. Curr Opin Hematol 2012 19(5) 392-8. 

Boiocchi L, Orazi A, Ghanima W, Arabadjief M, Bussel JB, Geyer JT. Thrombopoietin receptor agonist therapy in primary immune thrombocytopenia is associated with bone marrow hyperceUularity and mild reticuhn fibrosis but not other stromal abnormalities. Mod Pathol 2012 25(l) 65-74. 

Romiplostim, declared an orphan drug by the FDA in 2003, is an Fc fusion protein analogue of thrombopoietin and a thrombopoietin receptor agonist. The drug increases the number of platelets and restores platelet function making it a candidate for the treatment of chronic immune thrombocytopenia where a reported side-effect is its involvement in cases of stent thrombosis [68 ]. 

Rayoo R, Sharma N, van Gaal WJ. A case of acute stent thrombosis during treatment with the thrombopoietin receptor agonist peptide -romiplostim. Heart Lung Circ 2012 21(3) 182-4. 

Eltrombopag is a new orally active small molecule agonist at the thrombopoietin receptor licensed for use in idiopathic thrombocytopenia. Because of toxicity concerns, eltrombopag is restricted to use by registered physicians and patients. 

Antipas AS, Blumberg LC, Brissette WH et al (2010) Structure-activity relationships and hepatic safety risks of thiazole agonists of the thrombopoietin receptor. Biooig Med Chem Lett 20 4069-4077... 

A new xanthocillin 80 was isolated from marine fungus Basipetospora sp. as thrombopoietin (TPO) mimics. It promoted the proliferation of a TPO-sensitive human leukemia cell line, UT-7/TPO, and UT-7/EPO-mpl, genetically engineered to express c-Mpl, a receptor for TPO in dose-dependent manners. However, the proliferation of UT-7/EPO, a parental cell line of UT-7/EPO-mpl that was devoid of TPO receptor, was not affected by it. These data indicated that xanthocillin 80 is putative agonists for c-Mpl, as its cellular actions was analogous to those of TPO. 

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