Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro‐Oxindole Dihydroquinazolinones as IRAP Inhibitors

Insulin‐regulated aminopeptidase (IRAP) is a new potential macromolecular target for drugs aimed for treatment of cognitive disorders. Inhibition of IRAP by angiotensin IV (Ang IV) improves the memory and learning in rats. The majority of the known IRAP inhibitors are peptidic in character and suffer from poor pharmacokinetic properties. Herein, we present a series of small non‐peptide IRAP inhibitors derived from a spiro‐oxindole dihydroquinazolinone screening hit (pIC50 5.8). The compounds were synthesized either by a simple microwave (MW)‐promoted three‐component reaction, or by a two‐step one‐pot procedure. For decoration of the oxindole ring system, rapid MW‐assisted Suzuki‐Miyaura cross‐couplings (1 min) were performed. A small improvement of potency (pIC50 6.6 for the most potent compound) and an increased solubility could be achieved. As deduced from computational modelling and MD simulations it is proposed that the S‐configuration of the spiro‐oxindole dihydroquinazolinones accounts for the inhibition of IRAP. Inhibitors of insulin‐regulated aminopeptidase (IRAP) constitute a new potential class of cognitive enhancers. We herein report the SAR of a series of IRAP inhibitors encompassing a spiro‐oxindole dihydroquinazolinone scaffold and their tentative binding poses, as deduced from computational modelling and MD simulations. This series of compounds represents one of the few classes of small‐molecule based IRAP‐inhibitors exhibiting sub‐μM affinity.