A novel class of enkephalinase inhibitors containing a C-terminal sulfo group.
A new series of sulfonic acids were synthesized and tested for their enkephalinase inhibitory activity. Among them, the most potent was N-(2-benzyl-3-mercaptopropionyl)metanilic acid 10i with an IC50 value of 0.27 nM. Several other analogues (10a,b,j,n,o,gg,hh) showed the inhibitory activity comparable to or greater than thiorphan (IC50 = 2.6 nM), a C-terminal carboxyl-containing inhibitor of enkephalinase. Thus compounds containing a C-terminal sulfo group, instead of the C-terminal carboxyl group, were found to show a remarkably high level of inhibition of enkephalinase. The analgesic activity of 10b, (S)-10b, and (R)-10b was also evaluated by the phenylbenzoquinone writhing test.
Mimura
T
T
Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Nakamura
Y
Y
Nishino
J
J
Sawayama
T
T
Komiya
T
T
Deguchi
T
T
Kita
A
A
Nakamura
H
H
Matsumoto
J
J
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005260:Female; D051379:Mice; D008968:Molecular Conformation; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011817:Rabbits; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis / Q000494:pharmacology
D000700:Analgesics; D004791:Enzyme Inhibitors; D013451:Sulfonic Acids; D015260:Neprilysin