TY - JOUR
T1 - 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
AU - Imada, Takashi
AU - Cho, Nobuo
AU - Imaeda, Toshihiro
AU - Hayase, Yoji
AU - Sasaki, Satoshi
AU - Kasai, Shizuo
AU - Harada, Masataka
AU - Matsumoto, Hirokazu
AU - Endo, Satoshi
AU - Suzuki, Nobuhiro
AU - Furuya, Shuichi
PY - 2006/6/29
Y1 - 2006/6/29
N2 - 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.
AB - 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.
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U2 - 10.1021/jm0512894
DO - 10.1021/jm0512894
M3 - Article
C2 - 16789738
AN - SCOPUS:33745650903
VL - 49
SP - 3809
EP - 3825
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 13
ER -