Synthesis and phosphodiesterase inhibitory activity of new sildenafil analogues containing a carboxylic acid group in the 5′-sulfonamide moiety of a phenyl ring

Dae Kee Kim, Ju Young Lee, Namkyu Lee, Do Hyun Ryu, Jae Sun Kim, Sukho Lee, Jin Young Choi, Je Ho Ryu, Nam Ho Kim, Guang Jin Im, Won Son Choi, Tae Kon Kim

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Abstract

New sildenafil analogues possessing a carboxylic acid group in the 5' -sulfonamide of the phenyl ring, 9a l, were prepared from the readily available starting compounds 6a b and cyclic amines 3 5 in a three-step sequence. In the enzyme assays, it has been shown that all the target compounds 9a l proved to be more potent in inhibiting phosphodiesterase type 5 (PDE5) than sildenafil by 4 38-f ld. The effects on the 50 values were investigated by varying the alkoxy group (R) of the phenyl ring, the sulfonamide type (X), and the length of the methylene chain linking the carboxylic acid, and the results were discussed in detail. From this study, we have clearly demonstrated that introduction of a carboxylic acid group to the 5'-sulfonamide moiety of the phenyl ring greatly enhanced PDE5 inhibitory activity, probably by mimicking the phosphate group of cGMP. The piperidinyl propionic acid derivative 9i, which showed the highest PDE5 inhibitory activity and comparable to better selectivity over PDE isozymes in comparison with sildenafil, has been selected for more detailed biological investigations.

Original languageEnglish
Pages (from-to)3013-3021
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume9
Issue number11
DOIs
StatePublished - 2001

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