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

Engen K, Vanga SR, Lundbäck T, Agalo F, Konda V, Jensen AJ, Åqvist J, Gutiérrez-de-Terán H, Hallberg M, Larhed M, Rosenström U

ChemistryOpen 9 (3) 325-337 [2020-03-00; online 2020-03-02]

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 (pIC 50 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.

Chemical Biology Consortium Sweden (CBCS) [Collaborative]

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PubMed 32154052

DOI 10.1002/open.201900344

Crossref 10.1002/open.201900344

pii: OPEN201900344
pmc: PMC7050655