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

  • Bioorg Med Chem. 2023 Apr 15:84:117258. doi: 10.1016/j.bmc.2023.117258.
Willem F J Karstens  1 ,  Wiro M B P Menge  2 ,  Gijs Martens  2 ,  Sanne J N Op Het Veld  2 ,  Jacobus Th H van Eupen  2 ,  Marco Demon  2 ,  Tanja A E van Achterberg  2 ,  Monica J Arisse-Thijssen  2 ,  Ellen W H Santegoeds-Lenssen  2 ,  Miranda M C van der Lee  2 ,  Ruud Ubink  2 ,  Roel J Arends  2 ,  Aloys Sesink  2 ,  Marion Blomenröhr  3 ,  C Marco Timmers  2
Affiliations
  • 1. Byondis BV, Microweg 22, 6545 CM Nijmegen, The Netherlands. Electronic address: [email protected].
  • 2. Byondis BV, Microweg 22, 6545 CM Nijmegen, The Netherlands.
  • 3. Byondis BV, Microweg 22, 6545 CM Nijmegen, The Netherlands; Present address: Bone-Tech BV, Kloosterstraat 9, 5349 AB Oss, The Netherlands.
PMID: 37001244 DOI: 10.1016/j.bmc.2023.117258
Abstract

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.

Keywords
GPCR-antagonist; Graves’ disease; Small molecule antagonist; TSH-R antagonist; Thyroid stimulating hormone receptor; Thyrotropin receptor.
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