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

Takashi Imada, Nobuo Cho, Toshihiro Imaeda, Yoji Hayase, Satoshi Sasaki, Shizuo Kasai, Masataka Harada, Hirokazu Matsumoto, Satoshi Endo, Nobuhiro Suzuki, Shuichi Furuya

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

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)phen-yl] -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.

Original languageEnglish
Pages (from-to)3809-3825
Number of pages17
JournalJournal of medicinal chemistry
Volume49
Issue number13
DOIs
Publication statusPublished - Jun 29 2006
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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