Title of article :
Structure–activity relationships of a novel class of endothelin receptor selective antagonists; 6-carboxy-2-isopropylamino-5,7-diarylcyclopenteno[1,2-b]pyridines
Author/Authors :
Hirobumi Takahashi، نويسنده , , Norikazu Ohtake، نويسنده , , Toshihiro Sakamoto، نويسنده , , Tomoharu Iino، نويسنده , , Nobuhiko Kawanishi، نويسنده , , Masayuki Nakamura، نويسنده , , Takashi Yoshizumi، نويسنده , , Kenji Niiyama، نويسنده , , Satoshi Ozaki، نويسنده , , Hiromasa Okada، نويسنده , , Akiko Kano، نويسنده , , Hiroyuki Takahashi، نويسنده , , Yasuyuki Ishii، نويسنده , , Megumu Okada، نويسنده , , Michiyasu Saito، نويسنده , , Yoshio Sawazaki، نويسنده , , Takashi Hayama، نويسنده , , Masaru Nishikibe، نويسنده ,
Abstract :
The synthesis and structure–activity relationships of 6-carboxy-2-isopropylamino-5,7-diarylcyclopenteno[1,2-b]pyridine class of ETA receptor selective antagonists were described. These derivatives were prepared from the optically active key intermediates (3, 4, 10, and 13). Optimization of the substituent at the 2-position of the bottom 4-methoxyphenyl ring of the lead compound 1 led to identification of 2-hydroxy-1-methylethoxy (2g and h), hydroxyalkyl (2i, m, and p), 3-methoxy-2-methylpropyl (2t and u), N-acetyl-N-methylaminomethyl (2v), and 2-(dimethylcarbamoyl)propyl (2w) derivatives that showed greater than 1000-fold selectivity for the ETA receptor over the ETB receptor with excellent binding affinity (IC50<0.10 nM). Further screening of these compounds by assessing the plasma exposures at 1 h, 4 h, and 8 h after oral administration (3 or 10 mg/kg) in rats led to identification of the hydroxymethyl (2i) and 3-methoxy-2-methylpropyl (2u) derivatives exhibiting good oral bioavailability in rats.
