3-Amino-2-hydroxy-propionaldehyde and 3-amino-1-hydroxypropan-2-one derivatives: New classes of aminopeptidase inhibitors

Article abstract of DOI:10.1016/0968-0896(96)00115-0

3-Amino-2-hydroxy-propionaldehydes [H₂NCH(R)CHOHCHO with R = H, i-Bu, CH₂Ph] were designed as metalloaminopeptidase inhibitors based on the metal active site chelation concept. These compounds were found to be micromolar inhibitors of aminopeptidase-M (AP-M, EC 3.4.11.2) with potencies similar to bestatin (K(i) = 3.5 μM). Notably, compound 5a (R = H) is a selective inhibitor of AP-M (K(i) = 7 μM) with respect to cytosolic leucine aminopeptidase (LAPc, EC 3.4.11.1) (K(i) = 385 μM). However, due to their easy oligomerization, these compounds are of low practical value. In contrast, the corresponding isomeric 3-amino-1-hydroxy-propan-2-one derivatives [H₂NCH(R)COCH₂OH with R = H, i-Bu, CH₂Ph, i-Pr, CH₂Biph] are well defined structures. These hydroxymethylketones also exhibit micromolar affinities on AP-M. Compound 6c (R = CH₂Ph) was the most potent (K(i) = 1 μM). Selectivity studies of 6a (R = H) and 6b (R = i-Bu) show a preference for AP-M. Compound 6a is moderately active on AP-M (K(i) = 25 μM) and inactive on LAPc. This new class of inhibitors is proposed to bind as bidentates, analogous to hydroxamates.