Structure–Activity relationships of 2-substituted 5,7-Diarylcyclopenteno[1,2-b]pyridine-6-carboxylic acids as a novel class of endothelin receptor antagonists
作者:Kenji Niiyama、Hirobumi Takahashi、Toshio Nagase、Hisaki Kojima、Yuka Amano、Kasumi Katsuki、Takeru Yamakawa、Satoshi Ozaki、Masaki Ihara、Mitsuo Yano、Takahiro Fukuroda、Masaru Nishikibe、Kiyofumi Ishikawa
DOI:10.1016/s0960-894x(02)00663-7
日期:2002.11
lead structure 1 (IC(50)=2.4nM, 170-fold selectivity) by incorporating a substituent such as an alkyl, alkoxy, alkylthio, or alkylamino group into the 2-position of the cyclopenteno[1,2-b]pyridine skeleton was achieved via the key intermediate 8. Introduction of an alkyl group led to the identification of potent ET(A)/ET(B) mixed receptor antagonists, a butyl (2d: IC(50)=0.21nM, 52-fold selectivity)
描述了新型的内皮素受体拮抗剂2-取代的5,7-二芳基环戊烯[1,2-b]吡啶-6-羧酸的合成与构效关系。通过将取代基(例如烷基,烷氧基,烷硫基或烷基氨基)引入到环戊烯[1,2-b]的2位,衍生化铅结构1(IC(50)= 2.4nM,选择性170倍) ]吡啶骨架是通过关键中间体8实现的。烷基的引入导致鉴定出有效的ET(A)/ ET(B)混合受体拮抗剂,丁基(2d:IC(50)= 0.21nM,52-选择性)和异丁基(2f:IC(50)= 0.32nM,26倍选择性)类似物。相反,伯氨基的安装产生了ET(A)选择性拮抗剂,丙基氨基2p(IC(50)= 0.12nM,选择性520倍)和异丙氨基2q(IC(50)= 0)。10nM,选择性420倍)类似物。这些结果表明,在5,7-二芳基环戊烯[1,2-b]吡啶-6-羧酸的2-位上的取代基在与ET(A)和ET(B)的结合亲和力中起关键作用。受体。