517876-58-3Relevant articles and documents
Structure-activity relationships of 2-substituted 5,7-Diarylcyclopenteno[1,2-b]pyridine-6-carboxylic acids as a novel class of endothelin receptor antagonists
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
, p. 3041 - 3045 (2007/10/03)
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 (IC50=2.4 nM, 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 ETA/ETB mixed receptor antagonists, a butyl (2d: IC50=0.21 nM, 52-fold selectivity) and an isobutyl (2f: IC50=0.32 nM, 26-fold selectivity) analogue. In contrast, installment of a primary amino group resulted in ETA selective antagonists, a propylamino 2p (IC50=0.12 nM, 520-fold selectivity) and an isopropylamino 2q (IC50=0.10 nM, 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 ETA and ETB receptors.
