title: A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice.
abstract: Because the TSH receptor (TSHR) plays an important role in the pathogenesis of thyroid disease, a TSHR antagonist could be a novel treatment. We attempted to develop a small molecule, drug-like antagonist of TSHR signaling that is selective and active in vivo. We synthesized NCGC00242364 (ANTAG3) by chemical modification of a previously reported TSHR antagonist. We tested its potency, efficacy, and selectivity in a model cell system in vitro by measuring its activity to inhibit stimulation of cAMP production stimulated by TSH, LH, or FSH. We tested the in vivo activity of ANTAG3 by measuring its effects to lower serum free T4 and thyroid gene expression in female BALB/c mice continuously treated with ANTAG3 for 3 days and given low doses of TRH continuously or stimulated by a single administration of a monoclonal thyroid-stimulating antibody M22. ANTAG3 was selective for TSHR inhibition; half-maximal inhibitory doses were 2.1 μM for TSHR and greater than 30 μM for LH and FSH receptors. In mice treated with TRH, ANTAG3 lowered serum free T4 by 44% and lowered mRNAs for sodium-iodide cotransporter and thyroperoxidase by 75% and 83%, respectively. In mice given M22, ANTAG3 lowered serum free T4 by 38% and lowered mRNAs for sodium-iodide cotransporter and thyroperoxidase by 73% and 40%, respectively. In conclusion, we developed a selective TSHR antagonist that is effective in vivo in mice. This is the first report of a small-molecule TSHR antagonist active in vivo and may lead to a drug to treat Graves' disease.
authors.affiliation: Laboratory of Endocrinology and Receptor Biology (S.N., E.N., E.E., M.C.G.), National Institute of Diabetes and Digestive and Kidney Diseases, and Division of Pre-Clinical Innovation (W.H., J.M., J.X., A.E.D.), National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Susanne
authors.initials: S
authors.lastname: Neumann
authors.forename: Eshel A
authors.initials: EA
authors.lastname: Nir
authors.forename: Elena
authors.initials: E
authors.lastname: Eliseeva
authors.forename: Wenwei
authors.initials: W
authors.lastname: Huang
authors.forename: Juan
authors.initials: J
authors.lastname: Marugan
authors.forename: Jingbo
authors.initials: J
authors.lastname: Xiao
authors.forename: Andrés E
authors.initials: AE
authors.lastname: Dulcey
authors.forename: Marvin C
authors.initials: MC
authors.lastname: Gershengorn
mesh_terms: D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D006111:Graves Disease / Q000188:drug therapy; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D011989:Receptors, Thyrotropin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism*; D013972:Thyrotropin / Q000737:chemistry
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D008024:Ligands; C586517:NCGC00242364; D011989:Receptors, Thyrotropin; D013972:Thyrotropin