Discovery of thiochroman derivatives bearing a carboxy-containing side chain as orally active pure antiestrogens.
In order to search for alternatives to the sulfoxide moiety in the long side chain of pure antiestrogens, several molecules that may interact with water in a fashion similar to ICI164,384 were designed and it was found that compounds with the carboxy, the sulfamide, or the sulfonamide instead of the sulfoxide moiety also functioned as pure antiestrogens. Interestingly, the compound possessing the carboxy moiety showed superior antiestrogen activity compared to ICI182,780 when dosed orally. Results of the pharmacokinetic evaluation indicated that the potent antiestrogen activity at oral dosing attributed to both the improved absorption from the intestinal wall and the metabolic stability of the compound in liver.
Kanbe
Yoshitake
Y
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd, 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan. kanbeyst@chugai-pharm.co.jp
Kim
Myung-Hwa
MH
Nishimoto
Masahiro
M
Ohtake
Yoshihito
Y
Tsunenari
Toshiaki
T
Taniguchi
Kenji
K
Ohizumi
Iwao
I
Kaiho
Shin-ichi
S
Nabuchi
Yoshiaki
Y
Kawata
Setsu
S
Morikawa
Kazumi
K
Jo
Jae-Chon
JC
Kwon
Hee-An
HA
Lim
Hyun-Suk
HS
Kim
Hak-Yeop
HY
D000284:Administration, Oral; D019540:Area Under Curve; D002839:Chromans / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
D002839:Chromans; D020847:Estrogen Receptor Modulators