Discovery of SYD5115, a novel orally active small molecule TSH-R antagonist. (15th April 2023)

• Record Type: Journal Article
• Authors: Karstens, Willem F.J.; M.B.P. Menge, Wiro; Martens, Gijs; op het Veld, Sanne J.N.; Th.H. van Eupen, Jacobus; Demon, Marco; van Achterberg, Tanja A.E.; Arisse-Thijssen, Monica J.; Santegoeds-Lenssen, Ellen W.H.; van der Lee, Miranda M.C.; Ubink, Ruud; Arends, Roel J.; Sesink, Aloys; Blomenröhr, Marion; Marco Timmers, C.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 84(2023)
• Publication Date: 2023-04-15
• Subjects: Thyroid stimulating hormone receptor -- Thyrotropin receptor -- Small molecule antagonist -- TSH-R antagonist -- Graves' disease -- GPCR-antagonist; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2023.117258
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: 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. 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.