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Generated: January 23, 2018

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Title: Agonizing dimeric cell-surface receptors with a receptor binding moiety and chelating metal
Abstract:Dimeric cell-surface receptors in a subject are agonized by administering a metal chelated dimeric cell-surface receptor ligand formed by chelating a receptor binding moiety with a metal ion such as zinc, or by co-administering the receptor binding moiety and the metal ion. The binding moiety is a small organic molecule having a molecular weight of from about 100 to about 850, and metal chelation may form a symmetrical multimer such as a dimer of the receptor binding moiety. An example is bis{2,5-bis[2-benzimidazolylimino]-3a,6a-bis(2-pyridyl)-1,2,3,3a,4,5,6,6a- octahydroimidazo[4,5-d]imidazole-N,N'}-zinc(II). Dimeric cell surface receptors include granulocyte colony-stimulating factor, erythropoeitin receptor, macrophage-colony-stimulating factor, growth hormone receptor, thrombopoietin receptor, interferon alpha receptor, interferon beta receptor, tyrosine kinase receptor, insulin receptor and leptin receptor. A pharmaceutical composition containing a carrier and the ligand or the binding moiety and the metal ion separately can be used to enhance leukocyte production and to treat bacterial and fungal infections.
Inventor(s): Luengo; Juan I. (Audubon, PA), Miller; Stephen G. (San Diego, CA), Gleason; John G. (Downingtown, PA)
Assignee: SmithKline Beecham Corporation (Philadelphia, PA) Ligand Pharmaceuticals (San Diego, CA)
Filing Date:Apr 29, 1999
Application Number:09/301,897
Claims:1. A method for agonizing a dimeric cell surface receptor in a subject in need thereof which comprises administering, in separate dosage forms, to the subject a therapeutically effective amount of a receptor binding moiety and an amount of metal sufficient to form a metal chelate with said receptor binding moiety, wherein said receptor binding moiety is a ligand for said dimeric cell surface receptor when it is in metal chelated form and wherein said metal is selected from the group consisting of: iron, nickel, copper, manganese, magnesium, calcium, cobalt, cadmium, silver, paladium, ruthenium, chromium, vanadium, molybdenum and niobium.

2. The method of claim 1, wherein said dimeric cell surface receptor is selected from the group consisting of granulocyte colony-stimulating factor (G-CSF) receptor, erythropoeitin (EPO) receptor, macrophage-colony-stimulating factor (M-CSF) receptor, growth hormone (GRH) receptor, thrombopoietin (TPO) receptor, interferon (IFN) alpha receptor, interferon (IFN) beta receptor, and a tyrosine kinase (TRK) receptor.

3. The method of claim 2 wherein said cell surface receptor is a G-CSF receptor.
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