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 • Zheng, Wei • HUANG, Wenwei • Krause, Gerd • Kleinau, Gunnar
Assignees
Forschungsverbund Berlin FVB eV • US Department of Health and Human Services
Publication Number
US-9458141-B2
Publication Date
2016-10-04
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
Disclosed herein are low molecular weight compounds, specifically oxo-hydroquinazolines, that act as selective thyroid stimulating hormone receptor (TSHR) agonists. These compounds can be administered orally and are effective in activating the TSHR-mediated signaling pathway either by stimulating it directly or enhancing the biological activity of endogenous or exogenous TSHR agonists. The compounds have been demonstrated to selectively activate TSHR without modulating other hormone receptors such as LHCGR or FSHR, and may act as full agonists.
The problem addressed by the invention relates to the management and treatment of thyroid disorders and thyroid cancer. Currently, recombinant human TSH (rhTSH), a dimeric glycoprotein, is used clinically to stimulate iodide uptake in residual thyroid cancer cells to facilitate radioactive iodide therapy and for diagnostic screening after thyroidectomy. However, rhTSH is difficult to produce, requires stringent quality control, and must be administered parenterally. Patients undergoing withdrawal of thyroid hormone to elevate natural TSH levels experience unpleasant side effects. Therefore, there is a need for alternative, selective, and orally administrable TSHR agonists to improve detection and treatment of thyroid cancer and potentially other conditions.
The invention also discloses specific chemical structures, including compounds of formula I and formula VI, with defined substituents for use as TSHR agonists. Methods are provided for detecting thyroid cancer by administering these compounds to enhance radioiodine uptake or thyroglobulin serum levels, treating thyroid cancer alone or in combination with radioiodine, and treating or preventing bone degenerative disorders by therapeutically effective administration of these compounds. Pharmaceutical compositions comprising these compounds and their administration routes are also described.
Claims Coverage
The patent includes two independent claims: one directed to a compound with a specific chemical structure, and one directed to methods involving administration of such compounds for detecting and treating thyroid cancer.
Compound having a defined chemical structure as a TSHR agonist
A compound having a specific oxo-hydroquinazoline structure as described in formula I or formula VI, or a pharmaceutically acceptable salt thereof, with specified substituent groups (R1-R5, R15 as per formula II or III), capable of selectively activating the thyroid stimulating hormone receptor (TSHR). The compound can be substantially enantiomerically pure with an enantiomeric excess of 99% or greater.
Method for detecting thyroid cancer using the compound
A method involving administering a diagnostically effective amount of the compound to a subject suspected of thyroid cancer, optionally combined with administering radioiodine or measuring serum thyroglobulin levels, particularly in subjects who have undergone thyroidectomy for well-differentiated thyroid cancer. The administration enhances iodine uptake by thyroid cells or increases serum thyroglobulin.
Method for treating thyroid cancer with the compound
A method of treating thyroid cancer by administering a therapeutically effective amount of the compound alone or co-administered with radioiodine to ablate thyroid remnants following near-total thyroidectomy in subjects without evidence of metastatic disease.
The independent claims cover both the chemical compounds of defined structure serving as selective TSHR agonists and their therapeutic and diagnostic uses in detecting and treating thyroid cancer, including specific methods of administration that enhance iodide uptake and thyroglobulin levels, as well as ablation of thyroid remnants.
Stated Advantages
The compounds provide selective activation of TSHR without affecting related hormone receptors such as LHCGR or FSHR.
They can be orally administered, providing a more convenient alternative to injectable recombinant human TSH.
The compounds enable enhanced uptake of radioactive iodide by thyroid cells, improving the sensitivity of thyroid cancer detection and effectiveness of therapy.
They avoid the unpleasant side effects associated with thyroid hormone withdrawal currently required to elevate natural TSH levels.
Documented Applications
Detection of thyroid cancer by administration of the compounds to enhance radioiodine uptake and thyroglobulin serum testing after thyroidectomy.
Treatment of thyroid cancer, including adjunctive therapy with radioiodine to ablate residual thyroid tissue after near-total thyroidectomy.
Treatment or prevention of bone degenerative disorders, including but not limited to osteopenia, osteoporosis, osteomalacia, Paget’s disease, and bone loss associated with various conditions such as hypercalcemia, chronic renal disease, and corticosteroid use.
Use of the compounds in diagnostic assays involving activation of TSHR to assess thyroid function or cancer status.
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