A new highly thyrotropin receptor-selective small molecule antagonist with potential for the treatment of Graves' orbitopathy

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Item Type:	Article
Title:	A new highly thyrotropin receptor-selective small molecule antagonist with potential for the treatment of Graves' orbitopathy
Creators Name:	Marcinkowski, P., Hoyer, I., Specker, E., Furkert, J., Rutz, C., Neuenschwander, M., Sobottka, S., Sun, H., Nazare, M., Berchner-Pfannschmidt, U., von Kries, J.P., Eckstein, A., Schülein, R. and Krause, G.
Abstract:	The thyrotropin receptor (TSHR) is the target for autoimmune thyroid stimulating antibodies (TSAb) triggering hyperthyroidism. Whereas elevated thyroid hormone synthesis by the thyroid in Graves’ disease (GD) can be treated by anti-thyroid agents, for the pathogenic activation of TSHR in retro-orbital fibroblasts of the eye, leading to Graves’ orbitopathy (GO), no causal TSHR directed therapy is available. Due to the therapeutic gap for severe GO, we identified TSHR inhibitors by high-throughput screening in CHO cells expressing the TSHR. Stereo-selective synthesis of the screening hits led to the molecule S37 which contains seven chiral centers. Enantiomeric separation of the molecule S37 resulted in the enantiopure molecule S37a – a micro-molar antagonist of TSH-induced cAMP accumulation in HEK 293 cells expressing the TSHR. The unique rigid bent shape of molecule S37a may mediate the observed high TSHR selectivity: most importantly, the closely-related follitropin (FSH) and lutropin (LH) receptors were not affected by this compound. S37a not only inhibits the TSHR activation by TSH itself but also activation by monoclonal TSAb M22 (human), KSAb1 (murine) and the allosteric small molecule agonist C2. Disease-related ex vivo studies in HEK 293 cells expressing the TSHR showed that S37a also inhibits cAMP formation by oligoclonal TSAb, which are highly enriched in GO patients’ sera. Initial in vivo pharmacokinetic studies revealed no toxicity of S37a and a remarkable 53% oral bioavailability in mice. In summary, we present a novel highly selective inhibitor for the TSHR, which has promising potential for further development for the treatment of GO.
Keywords:	Thyrotropin Receptor, Graves' Disease, Graves' Orbitopathy, Small Molecule, Antagonist, Hyperthyroidism, Animals, Cricetinae, Cricetulus
Source:	Thyroid
ISSN:	1050-7256
Publisher:	Mary Ann Liebert
Volume:	29
Number:	1
Page Range:	111-123
Date:	23 January 2019
Official Publication:	https://doi.org/10.1089/thy.2018.0349
PubMed:	View item in PubMed

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