Thyroid Stimulating Hormone (TSH) is a heterodimeric glycoprotein hormone that regulates thyroid homeostasis upon interaction with the TSH receptor (TSHR). TSH binds to the TSH receptor, which couples preferentially to the G-alpha (s) (Gs) protein, resulting in activation of adenylate cyclase and an increase in cyclic adenosine 3′, 5′ monophosphate (cAMP). CID 2887926 is the first example of a small molecule TSHR inverse agonist. Preliminary structure-activity relationship studies led to the discovery of a selective TSHR inverse agonist, ML224, which could be a useful tool for studying TSHR functions; it could also be a potential lead for development of drugs to treat TSHR-mediated hyperthyroidism caused by constitutively activating mutations or stimulating auto-antibodies associated with Graves’ disease.