Potent and orally active ET(A) selective antagonists with 5,7-diarylcyclopenteno[1,2-b]pyridine-6-carboxylic acid structures.
The synthesis and structure-activity relationships of a series of 5,7-diarylcyclopenteno[1,2-b]pyridine-6-carboxylic acids are described. Our efforts have been focused on modification of the aryl ring at the 5-position and the alkyl substituent at the 2-position of the bottom 4-methoxyphenyl ring in an effort to develop orally available ET(A) selective antagonists with safer profiles in terms of the P-450 enzyme inhibitory activity. Incorporation of a hydroxymethyl group as an alkyl substituent in methylenedioxyphenyl and 6-dihydrobenzofuran derivatives led to the identification of orally bioavailable ET(A) selective antagonists 1f and 7f. These compounds also showed not only excellent binding affinity (IC(50) < 0.10nM, more than 800-fold selectivity for the ET(A) receptor over the ET(B) receptor) but also sufficient oral bioavailability, 48% and 56%, respectively, in rats. Furthermore, these compounds did not exhibit either competitive or mechanism-based inhibition of human cytochrome P450 enzymes.
Yoshizumi
Takashi
T
Banyu Tsukuba Research Institute in collaboration with Merck Research Laboratories, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan. yoszmitk@banyu.co.jp
Takahashi
Hirobumi
H
Ohtake
Norikazu
N
Jona
Hideki
H
Sato
Yoshiyuki
Y
Kishino
Hiroyuki
H
Sakamoto
Toshihiro
T
Ozaki
Satoshi
S
Takahashi
Hiroyuki
H
Shibata
Yoshihiro
Y
Ishii
Yasuyuki
Y
Saito
Michiyasu
M
Okada
Megumu
M
Hayama
Takashi
T
Nishikibe
Masaru
M
D000284:Administration, Oral; D001682:Biological Availability; D002264:Carboxylic Acids / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D065130:Endothelin A Receptor Antagonists; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship
D002264:Carboxylic Acids; D065607:Cytochrome P-450 Enzyme Inhibitors; D065130:Endothelin A Receptor Antagonists; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A