The main goal of this project is to develop a potent and selective small molecule TSHR antagonist that may have therapeutic potential for the treatment of Graves hyperthyroidism and GO and/or may also be useful as a probe for studies of TSHR function in extrathyroidal tissues. Additionally, a discovery of TSHR inverse agonist could benefit patients with non-autoimmune hyperthyroidism caused by constitutively activating germline mutations. During this period, the project team continued SAR-driven optimization of the lead molecule to improve metabolic stability. Pharmacokinetic studies were carried out, and the levels of T4 were also measured to corroborate activity of antagonists. Further optimization and scale-up is currently underway, with a view to testing the current best lead in the first-ever mouse model of Graves' Disease.
