Retro-inverso concept applied to the complete inhibitors of enkephalin-degrading enzymes

Article abstract of DOI:10.1021/jm00117a025

Peptide retro-inverso modification was applied to the complete hydroxamate inhibitors of the three zinc metallopeptidases (neutral endopeptidase 24-11 (NEP, EC 3.4.24.11), aminopeptidase N (APN, EC 3.4.11.2), and a dipeptidylaminopeptidase (DAP) involved in the in vitro enkephalin degradation by brain tissues. Compounds corresponding to the general formula RN(OH)CO(CH₂)(n)CH(CH₂Ph)NHCOCH(R')COOH (n=0, 1) were synthesized. In the first series of inhibitors (n=0), the 'retro-inverso' modification induced a large decrease in inhibitory potency for NEP as compared to that of the parent compounds. In contrast, the presence of a methylene group between the hydroxamate and CHα in the second series (n=1) led to derivatives with inhibitory potencies in the nanomolar range, similar to their analogues with a natural amide bond. On the other hand, the retro-inverso modification led to a slight improvement in the inhibition of DAP and APN, in the first series of inhibitors, while the inverse result occurred in the second series. Thus, compounds containing an α-amino acid moiety in P'₁ position behave as weak inhibitors of the three enzymes, with IC₅₀ values in the micromolar range, and compounds bearing a β-amino acid moiety in the same position are more specific than the parent compounds for NEP inhibition.