NEW HYDROXAMATE INHIBITORS OF NEUROTENSIN-DEGRADING ENZYMES - SYNTHESIS AND ENZYME ACTIVE-SITE RECOGNITION

Selective and mixed inhibitors of the three zinc metallopeptidases tha t degrade neurotensin (NT), e.g. endopeptidase 24-16 (EC 3.4.24.16), e ndopeptidase 24-11 (EC 3.4.24.11 or neutral endopeptidase, NEP) and en dopeptidase 24-15 (EC 3.4.24.15), and leucine-aminopeptidase (type IV- S), that degrades the NT-related peptides. Neuromedin N (NN), are of g reat interest. On the structural basis of compound JMV 390-1 ]-1-oxo-2 (R)-benzylpropyl]-L-isoleucyl-L-leucine), which was a full inhibitor o f the major NT degrading enzymes, several hydroxamate inhibitors corre sponding 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) w as nearly 40-times more potent in inhibiting EC 24-16 than NEP and mor e than 800-times more potent than EC 24-15, with an IC50 (12 nM) almos t equivalent to that of compound JMV 390-1. Therefore, this compound i s an interesting selective inhibitor of EC 24-16, and should be an int eresting probe to explore the physiological involvement of EC 24-16 in the metabolism of neurotensin. (C) Munksgaard 1996.