Takahashi Hirobumi, Ohtake Norikazu, Sakamoto Toshihiro, Iino Tomoharu, Kawanishi Nobuhiko, Nakamura Masayuki, Yoshizumi Takashi, Niiyama Kenji, Ozaki Satoshi, Okada Hiromasa, Kano Akiko, Takahashi Hiroyuki, Ishii Yasuyuki, Okada Megumu, Saito Michiyasu, Sawazaki Yoshio, Hayama Takashi, Nishikibe Masaru
Banyu Tsukuba Research Institute in collaboration with Merck Research Laboratories, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan.
Bioorg Med Chem Lett. 2004 Mar 22;14(6):1503-7. doi: 10.1016/j.bmcl.2004.01.008.
The synthesis and structure-activity relationships of 6-carboxy-2-isopropylamino-5,7-diarylcyclopenteno[1,2-b]pyridine class of ET(A) 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 ET(A) receptor over the ET(B) receptor with excellent binding affinity (IC(50)<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.
