title: Structure-Activity relationships of 2-substituted 5,7-Diarylcyclopenteno[1,2-b]pyridine-6-carboxylic acids as a novel class of endothelin receptor antagonists.
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.
authors.affiliation: Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd., 3 Okubo, Tsukuba, 300-2611, Ibaraki, Japan. niiyamakj@banyu.co.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Niiyama
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Toshio
authors.initials: T
authors.lastname: Nagase
authors.forename: Hisaki
authors.initials: H
authors.lastname: Kojima
authors.forename: Yuka
authors.initials: Y
authors.lastname: Amano
authors.forename: Kasumi
authors.initials: K
authors.lastname: Katsuki
authors.forename: Takeru
authors.initials: T
authors.lastname: Yamakawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ozaki
authors.forename: Masaki
authors.initials: M
authors.lastname: Ihara
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Yano
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fukuroda
authors.forename: Masaru
authors.initials: M
authors.lastname: Nishikibe
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Ishikawa
mesh_terms: D001667:Binding, Competitive / Q000187:drug effects; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D006801:Humans; D007202:Indicators and Reagents; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D011994:Recombinant Proteins; D013329:Structure-Activity Relationship
chemical_list: D003517:Cyclopentanes; D065128:Endothelin Receptor Antagonists; D007202:Indicators and Reagents; D011725:Pyridines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D011994:Recombinant Proteins