Rapid and efficient synthesis of a novel series of substituted aminobenzosuberone derivatives as potent, selective, non-peptidic neutral aminopeptidase inhibitors

Insight into the remarkable affinity and selectivity of the aminobenzosuberone scaffold for the M1 aminopeptidases family based on structure analysis

“…) as an interesting lead structure for competitive inhibition of this M1 family of “one‐zinc” aminopeptidases, due to its remarkable potency and selective profile toward the M17 and M18 isoforms that have a binuclear metal center, referred to as a co‐catalytic unit as well as all classes of proteolytic enzymes evaluated in the present work. Thus to elucidate the mode of binding of these previously proposed compounds we have determined the crystal structure of PepN in complex with three analogues that display various binding affinity constants (Ki µ M to n M ). These studies provide a molecular basis for their binding and a clear understanding of the Structure Activity Relationships (SAR) on PepN.…”

“…Amino-benzosuberone derivatives, shown in Figure 1, have proved to be highly selective and potent inhibitors of M1 mammalian APN/CD13. [27][28][29] The SAR determined on the human enzyme is very close to that determined on PepN (Table II). Even though the three derivatives evaluated are less potent on the bacterial enzyme (I1 (Ki 5 50 mM) is 25 times less active on the bacterial enzyme), the increase in inhibitory potency of the phenyl substituted analog I2 ($170-fold, Ki 5 0.33 mM) is very close for aminopeptidases from both species.…”

“…Amino‐benzosuberone derivatives, shown in Figure , have proved to be highly selective and potent inhibitors of M1 mammalian APN/CD13 . The SAR determined on the human enzyme is very close to that determined on PepN (Table ).…”

“…We hypothesized that the enzyme, via its catalytic hydrolytic activity, participates in the hydration reaction of the carbonyl to generate in situ a tetrahedral intermediate mimic, since the level of the ketone versus its hydrate form in solution (80:20) has no major influence on the Ki values. Indeed, the fluorinated analogue in the α‐position of the ketone, (85% in the hydrate form) did not show any significant improvement of binding affinity …”

Exploring S1 plasticity and probing S1′ subsite of mammalian aminopeptidase N/CD13 with highly potent and selective aminobenzosuberone inhibitors

“…According to the previously postulated binding model of aminobenzosuberone 1,6,7,14 we hypothesized that the active species would be the hydrated form of 1, which mimics the transition state intermediate formed during peptide bond hydrolysis. Therefore, the hydrated form of both enantiomers of 41 was docked into the active site of human APN (PDB entry 4FYT).…”