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8-(3-氯-4-甲氧基苄基)-8H-吡啶并[2,3-d]嘧啶-7-酮衍生物作为强效和选择性磷酸二酯酶5抑制剂

8-(3-chloro-4-methoxybenzyl)-8H-pyrido[2,3-d]pyrimidin-7-one derivatives as potent and selective phosphodiesterase 5 inhibitors.

作者信息

Sakamoto Toshiaki, Koga Yuichi, Hikota Masataka, Matsuki Kenji, Mochida Hideki, Kikkawa Kohei, Fujishige Kotomi, Kotera Jun, Omori Kenji, Morimoto Hiroshi, Yamada Koichiro

机构信息

Medicinal Chemistry Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.

Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.

出版信息

Bioorg Med Chem Lett. 2015 Apr 1;25(7):1431-5. doi: 10.1016/j.bmcl.2015.02.041. Epub 2015 Feb 21.

DOI:10.1016/j.bmcl.2015.02.041
PMID:25754491
Abstract

A novel series of highly selective phosphodiesterase 5 (PDE5) inhibitors was found. 8H-Pyrido[2,3-d]pyrimidin-7-one derivatives bearing an (S)-2-(hydroxymethyl)pyrrolidin-1-yl group at the 2-position and a 3-chloro-4-methoxybenzyl group at the 8-position exhibited potent PDE5 inhibitory activities and high PDE5 selectivity over PDE6. Among the synthesized compounds, the 5-methyl analogue (5b) showed the most potent relaxant effect on isolated rabbit corpus cavernosum with an EC30 value of 0.85 nM.

摘要

发现了一系列新型的高选择性磷酸二酯酶5（PDE5）抑制剂。在2位带有（S）-2-（羟甲基）吡咯烷-1-基且在8位带有3-氯-4-甲氧基苄基的8H-吡啶并[2,3-d]嘧啶-7-酮衍生物表现出强效的PDE5抑制活性，并且对PDE6具有高PDE5选择性。在合成的化合物中，5-甲基类似物（5b）对离体兔海绵体表现出最有效的舒张作用，EC30值为0.85 nM。

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