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.
['Engen|Karin|K|', 'Vanga|Sudarsana Reddy|SR|', 'Lundbäck|Thomas|T|0000-0002-8145-7808', 'Agalo|Faith|F|', 'Konda|Vivek|V|', 'Jensen|Annika Jenmalm|AJ|', 'Åqvist|Johan|J|', 'Gutiérrez-de-Terán|Hugo|H|', 'Hallberg|Mathias|M|', 'Larhed|Mats|M|0000-0001-6258-0635', 'Rosenström|Ulrika|U|0000-0002-0817-8140']
D000818:Animals D001665:Binding Sites D010122:Cystinyl Aminopeptidase D004353:Drug Evaluation, Preclinical D006801:Humans D008958:Models, Molecular D000078183:Oxindoles D011480:Protease Inhibitors D011485:Protein Binding D011487:Protein Conformation D052999:Quinazolinones D051381:Rats D011945:Receptors, Angiotensin D012995:Solubility D013329:Structure-Activity Relationship
inhibitors insulin-regulated aminopeptidases enzymes preclinical profiling spiro compounds