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-8741259-B2
Publication Date
2014-06-03
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 involves oxo-hydroquinazoline compounds that function as selective thyroid stimulating hormone receptor (TSHR) agonists. These low molecular weight compounds, represented by formula I and formula VI, activate the TSHR and are useful for diagnostic, analytical, and therapeutic purposes, including detecting or treating thyroid cancer and treating bone degenerative disorders.
The compounds specifically bind to the transmembrane domain of TSHR, enhancing or activating TSHR-mediated signaling pathways. They are orally administrable, selective for TSHR without activating related hormone receptors such as LHCGR or FSHR, and can act as full agonists. The disclosure also includes pharmaceutical compositions containing these compounds and methods for stimulating TSHR in vitro and in vivo.
The problem addressed arises from the limitations and difficulties in current TSHR agonist treatments. Thyroid cancer requires long term surveillance and treatment of residual tumor often involves radioactive iodide therapy. However, thyroid cancer cells poorly uptake iodine unless stimulated by TSH, which currently necessitates either withdrawal of thyroid hormone—causing unpleasant side effects—or administration of recombinant human TSH (rhTSH) that is difficult to produce and requires parenteral administration. The invention offers low molecular weight TSHR agonists that are easier to produce and can potentially be administered orally, overcoming difficulties with rhTSH treatment and hormone withdrawal.
Claims Coverage
The patent includes multiple independent claims pertaining to compounds of formula I and their pharmaceutical compositions. The main inventive features of these claims are extracted below.
Compounds of formula I as TSHR agonists
Compounds having formula I with specific substituent definitions, which function as thyroid stimulating hormone receptor agonists and selective agonists, including pharmaceutically acceptable salts thereof.
Pharmaceutical compositions comprising compound of formula I
Pharmaceutical compositions comprising at least one compound of formula I and a pharmaceutically acceptable carrier.
The claims cover novel oxo-hydroquinazoline compounds defined by formula I, their function as selective TSHR agonists, and pharmaceutical compositions including these compounds. The disclosure also covers specific structural features such as substituents and salt forms that contribute to their agonistic activity.
Stated Advantages
The compounds disclosed are selective TSHR agonists that do not activate related receptors LHCGR or FSHR.
They are low molecular weight and can be administered orally, unlike recombinant human TSH which requires parenteral administration.
They can be fully active agonists of TSHR, potentially improving efficacy.
They overcome the unpleasant side effects associated with thyroid hormone withdrawal currently needed to stimulate iodine uptake in thyroid cancer treatment.
Documented Applications
Detecting thyroid cancer by administering compounds to stimulate iodine uptake in thyroid cells to facilitate diagnostic imaging.
Treating thyroid cancer by administering therapeutically effective amounts of the compounds.
Treating or preventing bone degenerative disorders, such as osteopenia, osteoporosis, Paget's disease, and bone thinning conditions.
Use in pharmaceutical compositions for therapeutic, diagnostic, or prophylactic formulations.
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