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Synthesis,Evaluation and Proposed Binding Pose of Substituted Spiro-Oxindole Dihydroquinazolinones as IRAP Inhibitors |
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| Authors: | Karin Engen Dr Sudarsana Reddy Vanga Dr Thomas Lundbäck Dr Faith Agalo Vivek Konda Dr Annika Jenmalm Jensen Prof Johan Åqvist Dr Hugo Gutiérrez-de-Terán Prof Dr Mathias Hallberg Prof Dr Mats Larhed Dr Ulrika Rosenström |
| Institution: | 1. Department of Medicinal Chemistry, Uppsala University, SE-751 23 Uppsala, SWEDEN;2. Department of Cell and Molecular Biology, Uppsala University, SE-751 23 Uppsala, SWEDEN;3. Chemical Biology Consortium Sweden, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 65 Solna, SWEDEN;4. Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, SE-751 23 Uppsala, SWEDEN;5. The Beijer Laboratory, Department of Pharmaceutical Biosciences, Uppsala University, SE-751 23 Uppsala, SWEDEN;6. Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, SE-751 23 Uppsala, SWEDEN |
| 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. |
| Keywords: | enzymes inhibitors insulin-regulated aminopeptidases preclinical profiling spiro compounds |