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.
Subject(s)
Graves Disease , Receptors, Thyrotropin , Humans , Autoantibodies , Graves Disease/drug therapy , Receptors, G-Protein-Coupled , Receptors, Thyrotropin/antagonists & inhibitors , Thyrotropin/metabolismABSTRACT
The use of platinum drugs in antitumour therapy is well established. An important drawback of these chemotherapeutics is the lack of selectivity for tumour cells, usually resulting in severe toxic side effects. A glucuronyl-platinum conjugate was designed and synthesised to test the compatibility of platinum compounds with beta-glucuronidase-based prodrug therapy. Instantaneous cleavage of the beta-glucuronic bond in the glucuronyl-platinum conjugate was observed upon addition of beta-glucuronidase resulting in Pt(II)(dach)(4-hydroxybenzylmalonate) and glucuronic acid.
