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

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

  • Eur J Med Chem. 2022 Nov 15;242:114679. doi: 10.1016/j.ejmech.2022.114679.
Fangxia Zou 1,  Yao Wang 1,  Dawei Yu 2,  Chunjiao Liu 1,  Jing Lu 1,  Min Zhao 1,  Mingxu Ma 1,  Wenyan Wang 1,  Wanglin Jiang 3,  Yonglin Gao 1,  Rui Zhang 2,  Jianzhao Zhang 4,  Liang Ye 5,  Jingwei Tian 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, PR China.
  • 2 Medicinal Chemistry Research Department, R & D Center (Luye Pharma Group Ltd.), Yantai, 264003, PR China.
  • 3 School of Public Health and Management, Binzhou Medical University, Yantai, PR China.
  • 4 College of Life Sciences, Yantai University, Yantai, Shangdong, 264005, PR China. Electronic address: zhangjianzhao@163.com.
  • 5 School of Public Health and Management, Binzhou Medical University, Yantai, PR China. Electronic address: project0088@hotmail.com.
  • 6 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, PR China. Electronic address: Tianjingwei618@163.com.
PMID: 35998545 DOI: 10.1016/j.ejmech.2022.114679
Abstract

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.

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