Phosphinic derivatives as new dual enkephalin-degrading enzyme inhibitors: synthesis, biological properties, and antinociceptive activities.
The development of dual inhibitors of the two zinc metallopeptidases, neprilysin (neutral endopeptidase) and aminopeptidase N involved in the inactivation of the opioid peptides, enkephalins, represents an attractive physiological approach in the search for new analgesics devoid of the major drawbacks of morphine. Phosphinic compounds, corresponding to the general formula H(3)N(+)-CH(R(1))-P(O)(OH)-CH(2)-CH(R(2))-CONH-CH(R(3))-COO(-), able to act as transition-state analogues and to fit the S(1), S(1)', and S(2)' subsites of both enzymes were designed. Selection of the R(1), R(2), and R(3) residues for optimal recognition of these enzymes led to the first dual competitive inhibitors with K(i) values in the nanomolar range for neprilysin and aminopeptidase N. These compounds induce potent analgesic responses after intracerebroventricular or intravenous administrations in mice (hot plate test), and several of them were shown to be, at least, 10 times more potent than the previously described dual inhibitors.
Chen
H
H
Département de Pharmacochimie Moléculaire et Structurale, INSERM U266 - CNRS UMR 8600, UFR des Sciences Pharmaceutiques et Biologiques, Paris, France.
Noble
F
F
Mothé
A
A
Meudal
H
H
Coric
P
P
Danascimento
S
S
Roques
B P
BP
George
P
P
Fournié-Zaluski
M C
MC
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D018826:CD13 Antigens / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D004745:Enkephalins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D009682:Magnetic Resonance Spectroscopy; D008666:Metalloendopeptidases; D051379:Mice; D008968:Molecular Conformation; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010147:Pain Measurement; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012083:Renin / Q000378:metabolism; D013329:Structure-Activity Relationship
D000700:Analgesics; D004745:Enkephalins; D004791:Enzyme Inhibitors; D010721:Phosphinic Acids; D018826:CD13 Antigens; D016282:Aspartic Acid Endopeptidases; D012083:Renin; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes