Discovery of the thieno[2,3-d]pyrimidine-2,4-dione derivative 21a: A potent and orally bioavailable gonadotropin-releasing hormone receptor antagonist

The gonadotropin releasing hormone receptor (GnRH-R) is a G protein-coupled receptor (GPCR) belonging to the rhodopsin family. GnRH-R antagonists suppress testosterone to castrate level more rapidly than gonadotropin releasing hormone agonists but lack the flare phenomenon often seen during the early period of GnRH-R agonist treatment. Recently orgovyx (relugolix) was approved as the first oral GnRH-R antagonist for the treatment of advanced prostate Cancer. However, orgovyx has demonstrated poor pharmacokinetic profile with low oral bioavailability and high efflux. Here, we rationally designed and synthesized a series of derivatives (13a-m, 21a-i) through the modification and structure-activity relationship study of relugolix, which led to the discovery of 21a as a highly potent GnRH-R antagonist (IC₅₀ = 2.18 nM) with improved membrane permeability (Papp, A-B = 0.98 × 10^-6 cm/s) and oral bioavailability (F % = 44.7). Compound 21a showed high binding affinity (IC₅₀ = 0.57 nM) and potent in vitro antagonistic activity (IC₅₀ = 2.18 nM) at GnRH-R. 21a was well tolerated and efficacious in preclinical studies to suppress blood testosterone levels, which merits further investigation as a candidate novel GnRH-R antagonist for clinical studies.