title: Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor.
abstract: We previously discovered an orally active human gonadotropin-releasing hormone (GnRH) receptor antagonist, thieno[2,3-d]pyrimidine-2,4-dione derivative 1 (sufugolix). To reduce the cytochrome P450 (CYP) inhibitory activity and improve in vivo GnRH antagonistic activity, further optimization of this scaffold was carried out. We focused our synthetic efforts on chemical modification at the 5 and 3 positions of the thieno[2,3-d]pyrimidine-2,4-dione ring based on computational modeling, which resulted in the discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (16b) as a highly potent and orally active GnRH antagonist. Compound 16b showed potent in vitro GnRH antagonistic activity in the presence of fetal bovine serum (FBS) without CYP inhibition. Oral administration of 16b maintained the suppressive effect of the plasma luteinizing hormone levels in castrated cynomolgus monkeys at a 3 mg/kg dose for more than 24 h. Compound 16b is currently under clinical development with the code name of TAK-385.
authors.affiliation: CMC Center, Takeda Pharmaceutical Company, Ltd., 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan. Miwa_Kazuhiro@takeda.co.jp
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Miwa
authors.forename: Takenori
authors.initials: T
authors.lastname: Hitaka
authors.forename: Takashi
authors.initials: T
authors.lastname: Imada
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sasaki
authors.forename: Mie
authors.initials: M
authors.lastname: Yoshimatsu
authors.forename: Masami
authors.initials: M
authors.lastname: Kusaka
authors.forename: Akira
authors.initials: A
authors.lastname: Tanaka
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakata
authors.forename: Shuichi
authors.initials: S
authors.lastname: Furuya
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Hamamura
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kitazaki
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D003412:Cricetulus; D065692:Cytochrome P-450 CYP3A Inhibitors; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008958:Models, Molecular; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D013045:Species Specificity; D013329:Structure-Activity Relationship
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; C484844:GNRHR protein, human; D010671:Phenylurea Compounds; D011744:Pyrimidinones; D011966:Receptors, LHRH; C561634:relugolix