Low molecular weight thyroid stimulating hormone receptor (TSHR) agonists
Inventors
Gershengorn, Marvin C. • Neumann, Susanne • Raaka, Bruce M. • Thomas, Craig J. • Inglese, James • Southall, Noel T. • Titus, Steven • HUANG, Wenwei • Krause, Gerd • Kleinau, Gunnar • Zheng, Wei
Assignees
Forschungsverbund Berlin FVB eV • US Department of Health and Human Services
Publication Number
US-9296729-B2
Publication Date
2016-03-29
Expiration Date
2028-10-20
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Abstract
Disclosed are oxo-hydroquinazolines that are useful as selective TSHR agonists. The compounds may be used for detecting or treating thyroid cancer, or treating a bone degenerative disorder.
Core Innovation
The invention disclosed comprises oxo-hydroquinazolines that act as selective thyroid stimulating hormone receptor (TSHR) agonists. These low molecular weight compounds are useful for diagnostic, analytical, and therapeutic purposes, particularly for detecting or treating thyroid cancer and treating bone degenerative disorders. The compounds enhance or activate TSHR-mediated signaling pathways, and may be full agonists or selective agonists that do not activate other hormone receptors such as LHCGR and FSHR.
The problem being solved arises from the limitations of current thyroid cancer treatments and diagnostics. Thyroid cancer often requires the removal of most thyroid tumors followed by radioactive iodide therapy to ablate residual cells. However, thyroid cancer cells poorly uptake iodine, limiting the efficacy of radioactive iodine treatment. Presently, recombinant human TSH (rhTSH), a dimeric glycoprotein requiring complex production and parenteral administration, is used to stimulate iodide uptake for diagnostic screening and treatment. Withdrawal of thyroid hormone to raise natural TSH has significant side effects. There is a need for easily produced, orally administrable selective TSHR agonists that improve iodide uptake and aid in thyroid cancer detection and treatment without the drawbacks of rhTSH.
Claims Coverage
The patent contains three independent claims covering methods for detecting thyroid cancer, treating thyroid cancer, and treating bone degenerative disorders using compounds of formula I.
Method for detecting thyroid cancer using a TSHR agonist and radioiodine
A method comprising administering to a subject a diagnostically effective amount of radioiodine along with a diagnostically effective amount of at least one compound of formula I to enhance iodine uptake by thyroid cells for thyroid cancer detection, particularly in subjects post-thyroidectomy for well-differentiated thyroid cancer. The compound can be administered orally, and specific substituent groups are defined for formula I.
Method for treating thyroid cancer with TSHR agonists
A method involving administering a therapeutically effective amount of at least one compound of formula I to treat thyroid cancer in a subject. This method may include co-administering radioiodine to ablate thyroid remnants following near-total thyroidectomy in patients without metastatic disease. The claims specify particular substituents for formula I compounds and preferred structures.
Method for treating bone degenerative disorders using TSHR agonists
A method comprising administering a therapeutically effective amount of at least one compound having formula I to treat a bone degenerative disorder in a subject.
The independent claims cover methods of thyroid cancer detection and treatment, and bone degenerative disorder treatment, all employing compounds of formula I with specified substituents acting as selective TSHR agonists, alone or in combination with radioiodine when applicable.
Stated Advantages
The disclosed compounds are low molecular weight and can be orally administered, overcoming difficulties associated with recombinant human TSH production and parenteral administration.
Selective agonist activity for TSHR without activating related hormone receptors enhances safety and specificity.
The compounds increase iodine uptake by thyroid cells, allowing improved diagnostic sensitivity and therapeutic efficacy in thyroid cancer management.
Documented Applications
Thyroid cancer screening and diagnostics, including replacement of recombinant human TSH for screening residual or recurring thyroid cancer after surgery.
Treatment of thyroid cancer, including use in combination with radioiodine to ablate thyroid remnants post-thyroidectomy.
Treatment or prevention of bone degenerative disorders such as osteopenia, osteoporosis, osteomalacia, Paget's disease, and bone thinning following metastasis.
TSH stimulation to enhance PET scanning and chemotherapy treatment.
Differential diagnosis of congenital hypothyroidism.
Treatment of overweight or obesity by increasing metabolic rate of fat tissue.
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