Aminophosphinic inhibitors as transition state analogues of enkephalin-degrading enzymes: a class of central analgesics.
Inhibition of aminopeptidase N and neutral endopeptidase-24.11, two zinc metallopeptidases involved in the inactivation of the opioid peptides enkephalins, produces potent physiological analgesic responses, without major side-effects, in all animal models of pain in which morphine is active. Dual inhibitors of both enzymes could fill the gap between opioid analgesics and antalgics. Until now, attempts to find a compound with high affinity both for neutral endopeptidase and aminopeptidase N have failed. We report here the design of dual competitive inhibitors of both enzymes with KI values in the nanomolar range. These have been obtained by selecting R1, R2, and R3 determinants in aminophosphinic-containing inhibitors: NH2---CH(R1)P(O)---(OH)CH2---CH(R2)CONH---CH(R3)COOH, for optimal recognition of the two enkephalin inactivating enzymes, whose active site peculiarities, determined by site-directed mutagenesis, have been taken into account. The best inhibitors were 10x more potent than described dual inhibitors in alleviating acute and inflammatory nociceptive stimuli in mice, thus providing a basis for the development of a family of analgesics devoid of opioid side effects.
Chen
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H
Département de Pharmacochimie Moléculaire et Structurale, U 266 Institut National de la Santé et de la Recherche Médicale-Unité,de Paris, France.
Noble
F
F
Coric
P
P
Fournie-Zaluski
M C
MC
Roques
B P
BP
D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D018826:CD13 Antigens / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004745:Enkephalins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D009619:Nociceptors / Q000187:drug effects; D010146:Pain / Q000188:drug therapy; D010721:Phosphinic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship; D013552:Swine
D018712:Analgesics, Non-Narcotic; D004745:Enkephalins; D004791:Enzyme Inhibitors; D010721:Phosphinic Acids; D018826:CD13 Antigens; D015260:Neprilysin