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
Banyu Tsukuba Research Institute in collaboration with Merck Research Laboratories, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.
Bioorg Med Chem. 2004 May 1;12(9):2139-50. doi: 10.1016/j.bmc.2004.02.033.
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.
描述了一系列5,7 - 二芳基环戊烯并[1,2 - b]吡啶 - 6 - 羧酸的合成及其构效关系。我们致力于修饰5位的芳基环以及底部4 - 甲氧基苯基环2位的烷基取代基，以期开发出在P - 450酶抑制活性方面具有更安全特性的口服可用ET(A)选择性拮抗剂。在亚甲基二氧苯基和6 - 二氢苯并呋喃衍生物中引入羟甲基作为烷基取代基，从而鉴定出了口服生物可用的ET(A)选择性拮抗剂1f和7f。这些化合物不仅显示出优异的结合亲和力（IC(50) < 0.10 nM，对ET(A)受体的选择性比对ET(B)受体高800倍以上），而且在大鼠体内分别具有48%和56%的足够口服生物利用度。此外，这些化合物对人细胞色素P450酶既不表现出竞争性抑制，也不表现出基于机制的抑制作用。
