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Structure-Activity relationships of 2-substituted 5,7-Diarylcyclopenteno[1,2-b]pyridine-6-carboxylic acids as a novel class of endothelin receptor antagonists.

作者信息

Niiyama Kenji, Takahashi Hirobumi, Nagase Toshio, Kojima Hisaki, Amano Yuka, Katsuki Kasumi, Yamakawa Takeru, Ozaki Satoshi, Ihara Masaki, Yano Mitsuo, Fukuroda Takahiro, Nishikibe Masaru, Ishikawa Kiyofumi

机构信息

Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd., 3 Okubo, Tsukuba, 300-2611, Ibaraki, Japan.

出版信息

Bioorg Med Chem Lett. 2002 Nov 4;12(21):3041-5. doi: 10.1016/s0960-894x(02)00663-7.

DOI:10.1016/s0960-894x(02)00663-7
PMID:12372497
Abstract

Synthesis and structure-activity relationships of 2-substituted-5,7-diarylcyclopenteno[1,2-b]pyridine-6-carboxylic acids, a novel class of endothelin receptor antagonists, were described. Derivatization of a 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) and an isobutyl (2f: IC(50)=0.32nM, 26-fold selectivity) analogue. In contrast, installment of a primary amino group resulted in ET(A) selective antagonists, a propylamino 2p (IC(50)=0.12nM, 520-fold selectivity) and an isopropylamino 2q (IC(50)=0.10nM, 420-fold selectivity) analogue. These results suggested that a substituent at the 2-position of the 5,7-diarylcyclopenteno[1,2-b]pyridine-6-carboxylic acids played a key role in the binding affinity for both ET(A) and ET(B) receptors.

摘要

相似文献

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