title: Potent and orally active ET(A) selective antagonists with 5,7-diarylcyclopenteno[1,2-b]pyridine-6-carboxylic acid structures.
abstract: 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.
authors.affiliation: Banyu Tsukuba Research Institute in collaboration with Merck Research Laboratories, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan. yoszmitk@banyu.co.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshizumi
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Norikazu
authors.initials: N
authors.lastname: Ohtake
authors.forename: Hideki
authors.initials: H
authors.lastname: Jona
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Sato
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kishino
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ozaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Shibata
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ishii
authors.forename: Michiyasu
authors.initials: M
authors.lastname: Saito
authors.forename: Megumu
authors.initials: M
authors.lastname: Okada
authors.forename: Takashi
authors.initials: T
authors.lastname: Hayama
authors.forename: Masaru
authors.initials: M
authors.lastname: Nishikibe
mesh_terms: 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
chemical_list: D002264:Carboxylic Acids; D065607:Cytochrome P-450 Enzyme Inhibitors; D065130:Endothelin A Receptor Antagonists; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A