| 1. |
- Engen, Karin, et al.
(författare)
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Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro-oxindole Dihydroquinazolinones as IRAP Inhibitors
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Insulin-regulated aminopeptidase (IRAP, oxytocinase, EC 3.4.11.3) has been identified as a new potential macromolecular target for drugs aimed for treatment of cognitive disorders. Inhibition of the enzymatic activity by angiotensin IV (Ang IV) has been demonstrated to improve memory and learning in rats. The vast majority of the published inhibitors are peptides or pseudo-peptides often exhibiting high potencies but poor pharmacokinetic properties. Herein, a series of small non-peptide IRAP inhibitors are reported that are derived from a spiro-oxindole dihydroquinazolinone screening hit (pIC50 5.8). To obtain the target compounds either a fast and simple three-component reaction, or alternatively a two-step one-pot synthetic procedure was employed. Incorporation of various substituents at the oxindole-moiety could be performed by rapid microwave-assisted Suzuki-Miyaura cross-couplings in a reaction time of only one minute. The efforts led to a small improvement of potency (pIC50 6.6 for the most potent compound) and increased solubility in general, but attempts to enhance the metabolic stability were unproductive. A deeper understanding of the structure-activity relationships and of the mechanism of action of this series of IRAP inhibitors was obtained. Moreover, computational modeling and MD simulations of potential binding poses allowed us to strongly suggest that the S-configuration of the spiro-oxindole dihydroquinazolinones is the preferred stereochemistry when inhibiting IRAP.
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| 2. |
- Engen, Karin, et al.
(författare)
-
Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro-Oxindole Dihydroquinazolinones as IRAP Inhibitors
- 2020
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Ingår i: ChemistryOpen. - : Wiley. - 2191-1363. ; 9:3, s. 325-337
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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