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. Epub 2023 Mar 23.

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.

MeSH terms

  • Autoantibodies
  • Graves Disease* / drug therapy
  • Humans
  • Receptors, G-Protein-Coupled
  • Receptors, Thyrotropin* / antagonists & inhibitors
  • Thyrotropin / metabolism

Substances

  • Autoantibodies
  • Receptors, G-Protein-Coupled
  • Receptors, Thyrotropin
  • Thyrotropin
  • SYD5115