| Autor: |
Satoshi Ozaki, Toshio Nagase, Takahiro Fukuroda, Kazuhito Noguchi, Kasumi Katsuki, Kiyofumi Ishikawa, Kenji Niiyama, Takashi Hayama, Akihiro Hisaka, Masaki Ihara, Akira Naya, Hirobumi Takahashi, Satoshi Ito, Toshiaki Mase, Masaru Nishikibe, Mitsuo Yano |
| Rok vydání: |
2002 |
| Předmět: |
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| Zdroj: |
Bioorganic & Medicinal Chemistry. 10:2461-2470 |
| ISSN: |
0968-0896 |
| DOI: |
10.1016/s0968-0896(02)00122-0 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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Full Text from ScienceDirect