Design and synthesis of novel 5-(3,4,5-trimethoxybenzoyl)-4-aminopyrimidine derivatives as potent and selective phosphodiesterase 5 inhibitors: Scaffold hopping using a pseudo-ring by intramolecular hydrogen bond formation

作者：Sakamoto Toshiaki; Koga Yuichi; Hikota Masataka; Matsuki Kenji; Murakami Michino; Kikkawa Kohei; Fujishige Kotomi; Kotera Jun; Omori Kenji; Morimoto Hiroshi^*; Yamada Koichiro

来源：Bioorganic & Medicinal Chemistry Letters, 2014, 24(22): 5175-5180.

DOI：10.1016/j.bmcl.2014.09.082

• PDE5
• PDE6
• Erectile dysfunction
• Pseudo-ring
• Intramolecular hydrogen bond

5-(3,4,5-Trimethoxybenzoyl)-4-amimopyrimidine derivatives were found as a novel chemical class of potent and highly selective phosphodiesterase 5 inhibitors. A pseudo-ring formed by an intramolecular hydrogen bond constrained the conformation of 3-chloro-4-methoxybenzylamino and 3,4,5-trimethoxybenzoyl substituents and led to the discovery of T-6932 (19a) with a potent PDE5 inhibitory activity (IC50 = 0.13 nM) and a high selectivity over PDE6 (IC50 ratio: PDE6/PDE5 = 2400). Further modification at the 2-position of T-6932 resulted in the finding of 26, which exhibited potent relaxant effects on isolated rabbit corpus cavernosum (EC30 = 11 nM) with a high PDE5 selectivity over PDE6 (IC50 ratio: PDE6/PDE5 = 2800).

• 出版日期2014-11-15