Pharmacology of SCH 34826, an orally active enkephalinase inhibitor analgesic.
SCH 34826 [(S)-N-[N-[1-[[(2,2-dimethyl-1,3-dioxolan-4yl) methoxy]carbonyl]-2-phenylethyl]-L-phenylalanine]-beta-alanine] was synthesized as a p.o. active prodrug enkephalinase inhibitor. In vivo, it is de-esterified to SCH 32615 (N-[L-(-1-carboxy-2-phenyl)ethyl]-L-phenylalanyl-beta-alanine), the active constituent. In vitro, the Ki for SCH 32615 to block the degradation of Met5-enkephalin by isolated enkephalinase is 19.5 +/- 0.9 nM. In contrast, SCH 32615 did not inhibit aminopeptidase or diaminopeptidase III degradation of Met5-enkephalin up to 10 microM and did not affect angiotensin converting enzyme up to 10 microM. In vivo, p.o. administered SCH 34826 potentiated the analgesic effects of D-Ala2-Met5-enkephalinamide in mice (ED50 = 5.3 mg/kg p.o.) and rats [minimal effective dose (MED) = 1 mg/kg p.o.]; SCH 32615 had no effect up to 30 mg/kg p.o., but was active parenterally (ED50 in mice = 1.4 ng/kg sc). Direct, naloxone-reversible analgesic effects of SCH 34826 were demonstrated in the mouse low temperature hot-plate test (MED = 30 mg/kg p.o.), the mouse acetic acid-induced writhing test (MED = 30 mg/kg p.o.), the rat stress-induced analgesia test (MED = 10 mg/kg p.o.) and the modified rat yeast-paw test (MED = 100 mg/kg p.o.). Using the rat D-Ala2-Met5-enkephalinamide potentiation test the duration of action of SCH 34826 was at least 4 hs. No respiratory or gastrointestinal side effects of any consequence were noted at doses up to 100 times those active in the D-Ala2-Met-5-enkephalinamide potentiation test.
Chipkin
R E
RE
Research Division, Schering-Plough Corporation, Bloomfield, New Jersey.
Berger
J G
JG
Billard
W
W
Iorio
L C
LC
Chapman
R
R
Barnett
A
A
D000284:Administration, Oral; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004148:Dioxolanes / Q000494:pharmacology*; D004149:Dioxoles / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology*; D004357:Drug Synergism; D004744:Enkephalin, Methionine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D015260:Neprilysin; D051381:Rats; D012119:Respiration / Q000187:drug effects
D000700:Analgesics; D004148:Dioxolanes; D004149:Dioxoles; D004151:Dipeptides; C056319:Sch 34826; D009270:Naloxone; D004744:Enkephalin, Methionine; C022118:enkephalinamide-Met, Ala(2)-; D008666:Metalloendopeptidases; D015260:Neprilysin