Structure-activity relationships of a novel class of endothelin receptor selective antagonists; 6-carboxy-2-isopropylamino-5,7-diarylcyclopenteno[1,2-b]pyridines.
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.
Takahashi
Hirobumi
H
Banyu Tsukuba Research Institute in collaboration with Merck Research Laboratories, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan.
Ohtake
Norikazu
N
Sakamoto
Toshihiro
T
Iino
Tomoharu
T
Kawanishi
Nobuhiko
N
Nakamura
Masayuki
M
Yoshizumi
Takashi
T
Niiyama
Kenji
K
Ozaki
Satoshi
S
Okada
Hiromasa
H
Kano
Akiko
A
Takahashi
Hiroyuki
H
Ishii
Yasuyuki
Y
Okada
Megumu
M
Saito
Michiyasu
M
Sawazaki
Yoshio
Y
Hayama
Takashi
T
Nishikibe
Masaru
M
D000818:Animals; D065128:Endothelin Receptor Antagonists; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D011725:Pyridines / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017466:Receptors, Endothelin / Q000097:blood / Q000378:metabolism*; D013329:Structure-Activity Relationship
D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D017466:Receptors, Endothelin