title: New hydroxamate inhibitors of neurotensin-degrading enzymes. Synthesis and enzyme active-site recognition.
abstract: Selective and mixed inhibitors of the three zinc metallopeptidases that degrade neurotensin (NT), e.g. endopeptidase 24-16 (EC 3.4.24.16), endopeptidase 24-11 (EC 3.4.24.11 or neutral endopeptidase, NEP) and endopeptidase 24-15 (EC 3.4.24.15), and leucine-aminopeptidase (type IV-S), that degrades the NT-related peptides, Neuromedin N (NN), are of great interest. On the structural basis of compound JMV 390-1 (N-[3-[(hydroxyamino)carbonyl]-1-oxo-2(R)-benzylpropyl]-L- isoleucyl-L-leucine), which was a full inhibitor of the major NT degrading enzymes, several hydroxamate inhibitors corresponding to the general formula HONHCO-CH2-CH(CH2-C6H5)CO-X-Y-OH (with X-Y = dipeptide) have been synthesized. Compound 7a (X-Y = Ile-Ala) was nearly 40-times more potent in inhibiting EC 24-16 than NEP and more than 800-times more potent than EC 24-15, with an IC50 (12 nM) almost equivalent to that of compound JMV 390-1. Therefore, this compound is an interesting selective inhibitor of EC 24-16, and should be an interesting probe to explore the physiological involvement of EC 24-16 in the metabolism of neurotensin.
authors.affiliation: Laboratory of Aminoacids, Peptides and Proteins, LAPP, ESA CNRS 5075, Universities of Montpellier I and Montpellier II, Faculty of Pharmacy, France.
authors.forename: E
authors.initials: E
authors.lastname: Bourdel
authors.forename: S
authors.initials: S
authors.lastname: Doulut
authors.forename: G
authors.initials: G
authors.lastname: Jarretou
authors.forename: C
authors.initials: C
authors.lastname: Labbe-Jullie
authors.forename: J A
authors.initials: JA
authors.lastname: Fehrentz
authors.forename: O
authors.initials: O
authors.lastname: Doumbia
authors.forename: P
authors.initials: P
authors.lastname: Kitabgi
authors.forename: J
authors.initials: J
authors.lastname: Martinez
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006868:Hydrolysis; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D008666:Metalloendopeptidases / Q000378:metabolism*; D015260:Neprilysin / Q000378:metabolism*; D009496:Neurotensin / Q000378:metabolism*; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D009496:Neurotensin; D008666:Metalloendopeptidases; D015260:Neprilysin; C022510:thimet oligopeptidase; C062316:neurolysin