title: Design, synthesis, and structure-activity relationships of thieno[2,3-b]pyridin-4-one derivatives as a novel class of potent, orally active, non-peptide luteinizing hormone-releasing hormone receptor antagonists.
abstract: Design, synthesis, and structure-activity relationships of thieno[2,3-b]pyridin-4-one-based non-peptide luteinizing hormone-releasing hormone (LHRH) receptor antagonists are described. Starting with the thienopyridin-4-one derivative 26d (T-98475) an optimization study was performed, which resulted in the identification of a highly potent and orally bioavailable LHRH receptor antagonist, 3-(N-benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-4,7-dihydro-2-[4-(1-hydroxy-1-cyclopropanecarboxamido)phenyl]-5-isobutyryl-4-oxothieno[2,3-b]pyridine (33c). Compound 33c displayed subnanomolar in vitro activities for the human receptor and its oral administration caused effective suppression of the plasma LH levels in castrated male cynomolgus monkeys. Furthermore, SAR studies revealed that a hydroxyalkylamido moiety on the 2-phenyl ring is virtually equivalent to an alkylureido moiety, at least in this series of compounds.
authors.affiliation: Medicinal Chemistry Research Laboratories and Discovery Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan. Imada_Takashi@takeda.co.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Imada
authors.forename: Nobuo
authors.initials: N
authors.lastname: Cho
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Imaeda
authors.forename: Yoji
authors.initials: Y
authors.lastname: Hayase
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sasaki
authors.forename: Shizuo
authors.initials: S
authors.lastname: Kasai
authors.forename: Masataka
authors.initials: M
authors.lastname: Harada
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Matsumoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Suzuki
authors.forename: Shuichi
authors.initials: S
authors.lastname: Furuya
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C512436:3-(N-benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-4,7-dihydro-2-(4-(1-hydroxy-1-cyclopropanecarboxamido)phenyl)-5-isobutyryl-4-oxothieno(2,3-b)pyridine; D011725:Pyridines; D011728:Pyridones; D011966:Receptors, LHRH; D013876:Thiophenes; D016718:Arachidonic Acid