title: 6-Carboxy-5,7-diarylcyclopenteno[1,2-b]pyridine derivatives: a novel class of endothelin receptor antagonists.
abstract: Compounds (2-5) with a 6-carboxy-5,7-diarylcyclopentenopyridine skeleton were designed, synthesized, and identified as a new class of potent non-peptide endothelin receptor antagonists. The regio-isomer 2 was found to show potent inhibitory activity with an IC(50) value of 2.4 nM against (125)I-labeled ET-1 binding to human ET(A) receptors and a 170-fold selectivity for ET(A) over ET(B) receptors. Furthermore, 2 displayed more potent in vivo activity than did the indan-type compound 1 in a mouse ET-1 induced lethality model, suggesting the potential of 2 as a new lead structure. Derivatization on substituted phenyl groups at the 5- and 7-positions of 2 revealed that a 3,4-methylenedioxyphenyl group at the 5-position and a 4-methoxyphenyl group at the 7-position were optimal for binding affinity. Further derivatization of 2 by incorporating a substituent into the 2-position of the 4-methoxyphenyl group led to the identification of a more potent ET(A) selective antagonist 2p with an IC(50) value of 0.87 nM for ET(A) receptors and a 470-fold selectivity. In addition, 2p showed highly potent in vivo efficacy (AD(50): 0.04 mg/kg) in the lethality model.
authors.affiliation: Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan. niiymakj@banyu.co.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Niiyama
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Mase
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Akira
authors.initials: A
authors.lastname: Naya
authors.forename: Kasumi
authors.initials: K
authors.lastname: Katsuki
authors.forename: Toshio
authors.initials: T
authors.lastname: Nagase
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ito
authors.forename: Takashi
authors.initials: T
authors.lastname: Hayama
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hisaka
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: Kazuhito
authors.initials: K
authors.lastname: Noguchi
authors.forename: Masaru
authors.initials: M
authors.lastname: Nishikibe
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Ishikawa
mesh_terms: D000818:Animals; D065128:Endothelin Receptor Antagonists; D006801:Humans; D007083:Iliac Artery; D020128:Inhibitory Concentration 50; D007408:Intestinal Absorption; D007457:Iodine Radioisotopes; D051379:Mice; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013329:Structure-Activity Relationship; D015996:Survival Rate
chemical_list: D065128:Endothelin Receptor Antagonists; D007457:Iodine Radioisotopes; D011725:Pyridines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B