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-9187457-B2
Publication Date
2015-11-17
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 oxo-hydroquinazoline compounds useful as selective thyroid stimulating hormone receptor (TSHR) agonists suitable for diagnostic, analytical, and therapeutic purposes. These low molecular weight compounds, preferably less than 1000 daltons, activate TSHR and may be orally administered. They demonstrate selectivity by not activating other hormone receptors such as LHCGR and FSHR and can be full agonists for TSHR.
The problem addressed is that thyroid cancer frequently recurs in up to 30% of patients even after successful therapy, requiring long-term surveillance. Current recombinant human TSH (rhTSH) used for screening and stimulating iodine uptake in residual thyroid cancer is a dimeric glycoprotein that is difficult to produce, requires stringent quality control, and must be administered parenterally. Additionally, withdrawal of thyroid hormone treatment to elevate endogenous TSH levels causes unpleasant side effects. Thus, there is a need for selective, easily administered TSHR agonists to improve thyroid cancer detection and treatment.
The invention provides compounds with a defined chemical formula involving oxo-hydroquinazoline scaffolds with various substituents. These compounds selectively activate the TSH receptor both in vitro, as demonstrated in TSHR-expressing HEK293 cells and primary human thyrocytes, and in vivo, increasing serum thyroxine levels in mice. Methods involving administering these compounds include detecting thyroid cancer, treating thyroid cancer, preventing or treating bone degenerative disorders, and activating TSHR in assays. Pharmaceutical compositions comprising these compounds and suitable carriers are also disclosed.
Claims Coverage
The patent includes three main independent claims covering the compound structure, its diagnostic method for thyroid cancer, and its therapeutic method for thyroid cancer treatment. The following inventive features are extracted from these claims.
Compound defined by formula I as TSHR agonist
The invention claims a compound having formula I defined by specific substituent groups R1-R5, A, R15, and X with certain numerical and chemical constraints, wherein the compound functions as a thyroid stimulating hormone receptor agonist and is selective for TSHR.
Method for detecting thyroid cancer using the compound
A method of detecting thyroid cancer in a subject by administering a diagnostically effective amount of the compound of formula I along with a diagnostically effective amount of radioiodine, where the compound enhances iodine uptake by thyroid cells and is used particularly in subjects who have undergone thyroidectomy for well-differentiated thyroid cancer.
Method for treating thyroid cancer using the compound
A method for treating thyroid cancer by administering a therapeutically effective amount of the compound of formula I, optionally co-administering radioiodine (e.g., I-131) to ablate thyroid remnants following near-total thyroidectomy in subjects without metastatic disease.
The claims cover compounds specified by a defined formula that act as selective TSHR agonists and methods employing these compounds for thyroid cancer detection and treatment, including use with radioiodine for enhanced iodine uptake and ablation.
Stated Advantages
The low molecular weight compounds can be orally administered unlike recombinant human TSH which requires parenteral administration.
Selective TSHR activation without affecting other hormone receptors improves targeting and reduces off-target effects.
The compounds can enhance radioiodine uptake in thyroid cells, thereby improving detection sensitivity for thyroid cancer.
The compounds may alleviate unpleasant symptoms associated with thyroid hormone withdrawal currently used to elevate endogenous TSH levels.
Documented Applications
Screening for residual or recurrent thyroid cancer after thyroidectomy in patients with well-differentiated thyroid cancer, potentially replacing recombinant human TSH.
Adjunct diagnostic use in serum thyroglobulin testing for thyroid cancer monitoring.
Treatment and prevention of bone degenerative disorders including osteopenia, osteoporosis, osteomalacia, Paget's disease, osteogenesis imperfecta, and bone thinning following metastasis.
Therapeutic use in stimulating radioiodine uptake to ablate thyroid remnants post near-total thyroidectomy without metastatic disease.
Activation of TSH receptor in assays for diagnostic or research purposes.
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