Small-Molecule Modulators of the Thyroid-Stimulating Hormone (TSH) Receptor
Description of Invention:
The thyroid gland plays a major role in the body, secreting hormones that regulate the metabolic rate, production of other hormones, and the growth and maturation of body tissues. Thyroid disorders affect energy metabolism, neurological state, fertility, cardiovascular condition, and other body functions. In patients with hyperthyroidism, or an overactive thyroid gland, the disease is often caused by autoimmune over-stimulation of the thyroid gland (Graves’ disease), or by thyroid tumors. Drugs currently used for short-term treatment of hyperthyroidism inhibit synthesis of thyroid hormones, although long-term treatment usually requires removal of the thyroid gland by surgery or administration of radioiodine. Hypothyroidism, or an underactive thyroid gland, can be caused by autoimmune disease, atrophy of the thyroid gland, or through a deficiency of thyroid-stimulating hormone (TSH). TSH, produced by the pituitary gland, binds to the TSH receptor in the thyroid to stimulate thyroid hormone production. Hypothyroidism is typically treated by direct replacement of the thyroid hormones.
The inventors have discovered a series of low-molecular weight compounds that act as TSH receptor antagonists (inhibitors) or agonists (activators). Antagonists of the TSH receptor could be used to treat hyperthyroidism, with the advantage of directly downregulating the TSH receptor, rather than inhibiting thyroid hormone synthesis. Agonists of the TSH receptor could be used to monitor thyroid activity and potential cancer recurrence in patients who have been treated for thyroid cancer, and may also be useful for treatment of certain forms of hypothyroidism. Additionally, some compounds in this family may be useful for treatment of fertility and reproductive disorders involving the luteinizing hormone/choriogonadotropin (LH/CG) receptor and the follicle-stimulating hormone (FSH) receptor, which are structurally related to the TSH receptor.
Applications:
Development of therapeutics for hyperthyroidism or hypothyroidism.
Development of diagnostic tools for evaluation of thyroid cancer patients.
Development of therapeutics for infertility.
Market:
Approximately 1 in 13 Americans suffers from a thyroid disorder, and 10 million have a thyroid-related condition that requires ongoing immunodiagnostic monitoring.
Patent Status:
DHHS Reference No. E-223-2006/0 --
International Patent Application No. PCT/US2007/011951 filed 17 May 2007
Relevant Publication:
S Moore, H Jaeschke, G Kleinau, S Neumann, S Costanzi, JK Jiang, J Childress, BM Raaka, A Colson, R Paschke, G Krause, CJ Thomas, MC Gershengorn. Evaluation of small-molecule modulators of the luteinizing hormone/choriogonadotropin and thyroid stimulating hormone receptors: structure-activity relationships and selective binding patterns. J Med Chem. 2006 Jun 29;49(13):3888-3896. [PubMed abs]
S Titus, S Neumann,W Zheng, N Southall, S Michael, C Klumpp, A Yasgar, P Shinn, CJ Thomas, J Inglese, MC Gershengorn, CP Austin. Quantitative high throughput screening using a live cell cAMP assay identifies small molecule agonists of the TSH receptor. J Biomol Screen. 2008 Feb;13(2):120-127. [PubMed abs]
S Neumann, G Kleinau, S Costanzi, S Moore, BM Raaka, CJ Thomas, G Krause, MC Gershengorn: A low molecular weight antagonist for the human thyrotropin receptor with therapeutic potential for hyperthyroidism. Endocrinology. 2008 31 Jul; published online ahead of print, doi:10.1210/en.2008-0836. [PubMed abs]
Licensing Status: This technology is available for exclusive, co-exclusive, or nonexclusive licensing.
For Additional Information Please Contact: Tara L. Kirby Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd, Suite 325
Rockville, MD 20852-3804
Phone: (301)435-4426
Email: tarak@mail.nih.gov
Fax: (301)402-0220
