Potent and orally active ET(A) selective antagonists with 5,7-diarylcyclopenteno[1,2-b]pyridine-6-carboxylic acid structures |
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Authors: | Yoshizumi Takashi Takahashi Hirobumi Ohtake Norikazu Jona Hideki Sato Yoshiyuki Kishino Hiroyuki Sakamoto Toshihiro Ozaki Satoshi Takahashi Hiroyuki Shibata Yoshihiro Ishii Yasuyuki Saito Michiyasu Okada Megumu Hayama Takashi Nishikibe Masaru |
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Affiliation: | Banyu Tsukuba Research Institute in collaboration with Merck Research Laboratories, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan. yoszmitk@banyu.co.jp |
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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. |
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