Abstract
Drugs activating gonadotropin-releasing hormone （GnRH） receptor, GnRH analogs （agonists and antagonists）, have been clinically applied as therapeutic agents for sex-hormone related diseases. GnRH antagonists could be safer therapeutic agents without symptom exacerbation found in agonists. However, all previously launched GnRH antagonists were peptide drugs and were limited to injections. The development of orally available non-peptide GnRH antagonists therefore has been expected. We have previously found the thienopyrimidine compound TAK-013 based on small molecule studies focusing on the β-turn structure of GnRH. TAK-013 showed high GnRH binding affinity, but it is necessary to reduce the risk of CYP3A4 inhibition and improve in vivo activities of TAK-013. Further optimization of substituent was performed using the information of molecular modeling with GnRH receptor and considering the reduction in Log D value and molecular weight, and we finally discovered TAK-385 （Relugolix）, which has potent GnRH antagonistic in vivo activity.
