Synthesis and phosphodiesterase inhibitory activity of new sildenafil analogues containing a carboxylic acid group in the 5'-sulfonamide moiety of a phenyl ring.
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-fold. The effects on the IC(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.
Kim
D K
DK
Life Science Research Center, SK Chemicals, 600 Jungja-Dong, Changan-Ku, Suwon-Si, 440-745, Kyungki-Do, South Korea. dkkim@skchemicals.com
Lee
J Y
JY
Lee
N
N
Ryu
D H
DH
Kim
J S
JS
Lee
S
S
Choi
J Y
JY
Ryu
J H
JH
Kim
N H
NH
Im
G J
GJ
Choi
W S
WS
Kim
T K
TK
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry; D002417:Cattle; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004353:Drug Evaluation, Preclinical; D007172:Erectile Dysfunction / Q000188:drug therapy; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011687:Purines; D011817:Rabbits; D000068677:Sildenafil Citrate; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D013450:Sulfones
D002264:Carboxylic Acids; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D013450:Sulfones; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human