New orally active enkephalinase inhibitors: their synthesis, biological activity, and analgesic properties.
A series of (4S)-4-[(2S)-benzyl-3-mercaptopropionylamino]-4-(N-phenylcarbamoyl )-butyric acids has been identified as potent systemically active enkephalinase inhibitors. Structure-activity relationships (SAR) are discussed. Further chemical modification of the inhibitors was carried out in order to identify the inhibitors which are orally active in an animal model. Compounds of particular interest are the prodrug-like analogues, including 5b (ONO-9902). Their analgesic effects after oral administration were evaluated.
Senokuchi
K
K
Department of Medicinal Chemistry, Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
Nakai
H
H
Nagao
Y
Y
Sakai
Y
Y
Katsube
N
N
Kawamura
M
M
D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002087:Butyrates / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004285:Dogs; D004745:Enkephalins; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010147:Pain Measurement; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D002087:Butyrates; D004745:Enkephalins; D004791:Enzyme Inhibitors; C104138:ONO 9902; D011355:Prodrugs; D015260:Neprilysin