S37a

S37a is a novel, highly selective small-molecule antagonist and negative allosteric modulator (NAM) of the thyrotropin receptor (TSHR). It inhibits TSHR activation by thyrotropin itself as well as by monoclonal thyroid-stimulating antibodies (TSAb) such as M22 (human) and KSAb1 (murine), and also blocks activation by an allosteric small-molecule agonist C2. The compound binds at the ectodomain/transmembrane domain interface of TSHR. It has potential therapeutic application in treating Graves' orbitopathy, a condition caused by pathogenic activation of TSHR in retro-orbital fibroblasts leading to eye disease associated with Graves' disease. Preclinical studies demonstrated micromolar potency for inhibition of cyclic adenosine monophosphate accumulation induced by TSHR stimulation in HEK293 cells expressing human or mouse TSHR, with IC50 values around 20-40 μM. Ex vivo studies showed inhibition of cAMP formation triggered by oligoclonal TSAb from patients’ sera with Graves' orbitopathy. Pharmacokinetic data indicate no toxicity and about 53% oral bioavailability in mice. The molecule’s rigid bent shape contributes to its high selectivity for TSHR without affecting related receptors like follitropin or lutropin receptors.