Discovery of SYD5115, a novel orally active small molecule TSH-R antagonist

[Display omitted] •Discovery of a novel class of thyrotropin receptor antagonists.•A highly potent compound with oral efficacy was identified.•Risk of mutagenicity of compounds strongly reduced.•Efficacy correlates with exposure after oral dosing. The thyrotropin receptor (TSH-R) regulates the thyroid gland and is normally activated by thyrotropin. In patients with Graves’ disease, TSH-R is also stimulated by stimulatory TSH-R autoantibodies leading to hyperthyroidism. In this paper, we describe the discovery of SYD5115 (67), a novel small molecule TSH-R antagonist with nanomolar potency. SYD5115 also blocks stimulating antibody induced synthesis of the thyroid hormone thyroxine (T4) in vivo, after a single oral dose. During optimization, several issues had to be addressed such as the low metabolic stability and the potential mutagenicity of our first series of compounds.