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

Engen, Karin; Vanga, Sudarsana Reddy; Lundbäck, Thomas; Agalo, Faith; Konda, Vivek; Jensen, Annika Jenmalm; Åqvist, Johan; Gutiérrez‐de‐Terán, Hugo; Hallberg, Mathias; Larhed, Mats; Rosenström, Ulrika

doi:10.1002/open.201900344

Cited by 11 publications

(16 citation statements)

References 54 publications

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“…Efforts to improve the poor solubility of hit compound 12 (e.g. compound 13, Figure 2) led in all cases to derivatives with reduced metabolic stability in vitro (Engen et al, 2020). Nevertheless, this class of compounds presents high specificity for IRAP vs APN.…”

Section: Spiro-oxindole Dihydroquinazolinonesmentioning

confidence: 99%

The Discovery of Insulin-Regulated Aminopeptidase (IRAP) Inhibitors: A Literature Review

et al. 2020

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Insulin-Regulated Aminopeptidase (IRAP, EC 3.4.11.3) is a multi-tasking member of the M1 family of zinc aminopeptidases. Among its diverse biological functions, IRAP is a regulator of oxytocin levels during late stages of pregnancy, it affects cellular glucose uptake by trafficking of the glucose transporter type 4 and it mediates antigen crosspresentation by dendritic cells. Accumulating evidence show that pharmacological inhibition of IRAP may hold promise as a valid approach for the treatment of several pathological states such as memory disorders, neurodegenerative diseases, etc. Aiming to the investigation of physiological roles of IRAP and therapeutic potential of its regulation, intense research efforts have been dedicated to the discovery of small-molecule inhibitors. Moreover, reliable structure-activity relationships have been largely facilitated by recent crystal structures of IRAP and detailed computational studies. This review aims to summarize efforts of medicinal chemists toward the design and development of IRAP inhibitors, with special emphasis to factors affecting inhibitor selectivity.

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Section: Spiro-oxindole Dihydroquinazolinonesmentioning

confidence: 99%

The Discovery of Insulin-Regulated Aminopeptidase (IRAP) Inhibitors: A Literature Review

et al. 2020

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“…This proposal was supported by the essentially perfect correlation for binding affinity differences between the selected pair of compounds obtained by rigorous free energy perturbation calculations by Gutierrez-de-Teran's group (Vanga et al, 2018). In addition to the sulfonamides, e.g., 40 and 41, the spirooxindole dihydroquinazolinone derivative 42 was identified in the screening campaign and subsequently a large series of related analogues were made, e.g., by applying rapid MW-assisted reactions and thereafter examined as IRAP inhibitors in bioassays (Engen et al, 2020) (Figure 10). Compounds that were selective toward the closely related APN and that exhibited sub-μM affinity were identified.…”

Section: Small Molecule Insulin-regulated Aminopeptidase Inhibitors Fmentioning

confidence: 99%

“…In addition to the sulfonamides, e.g., 40 and 41 , the spiro-oxindole dihydroquinazolinone derivative 42 was identified in the screening campaign and subsequently a large series of related analogues were made, e.g., by applying rapid MW-assisted reactions and thereafter examined as IRAP inhibitors in bioassays ( Engen et al, 2020 ) ( Figure 10 ). Compounds that were selective toward the closely related APN and that exhibited sub-μM affinity were identified.…”

Section: Small Molecule Insulin-regulated Aminopeptidase Inhibitors Fmentioning

confidence: 99%

“…Notably, the proposed binding mode is compatible with the simultaneous binding of the substrate L-Leu- p NA, in agreement with the uncompetitive IRAP inhibition determined for a representative compound. Unfortunately, the compounds suffer from poor in vitro metabolic stability ( Engen et al, 2020 ).…”

Section: Small Molecule Insulin-regulated Aminopeptidase Inhibitors Fmentioning

confidence: 99%

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From Angiotensin IV to Small Peptidemimetics Inhibiting Insulin-Regulated Aminopeptidase

Hallberg

Larhed

2020

Front. Pharmacol.

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It was reported three decades ago that intracerebroventricular injection of angiotensin IV (Ang IV, Val-Tyr-Ile-His-Pro-Phe) improved memory and learning in the rat. There are several explanations for these positive effects of the hexapeptide and related analogues on cognition available in the literature. In 2001, it was proposed that the insulinregulated aminopeptidase (IRAP) is a main target for Ang IV and that Ang IV serves as an inhibitor of the enzyme. The focus of this review is the efforts to stepwise transform the hexapeptide into more drug-like Ang IV peptidemimetics serving as IRAP inhibitors. Moreover, the discovery of IRAP inhibitors by virtual and substance library screening and direct design applying knowledge of the structure of IRAP and of related enzymes is briefly presented.

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“…Possible reasons include limited selectivity, limited pharmacodynamics or deficient pharmacokinetics. Up to now, most efforts on developing IRAP inhibitors have either targeted the active site or utilized random library screening [ 10 , 11 , 12 ]. However, the IRAP active site is highly homologous to other aminopeptidases of the M1 family and is characterized by structural plasticity that could complicate the development of potent and selective inhibitors [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Discovery of Selective Inhibitor Leads by Targeting an Allosteric Site in Insulin-Regulated Aminopeptidase

et al. 2021

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Insulin-Regulated aminopeptidase (IRAP) is a zinc-dependent aminopeptidase with several important biological functions and is an emerging pharmaceutical target for cognitive enhancement and immune system regulation. Aiming to discover lead-like IRAP inhibitors with enhanced selectivity versus homologous enzymes, we targeted an allosteric site at the C-terminal domain pocket of IRAP. We compiled a library of 2.5 million commercially available compounds from the ZINC database, and performed molecular docking at the target pocket of IRAP and the corresponding pocket of the homologous endoplasmic reticulum aminopeptidase 1 (ERAP1). Of the top compounds that showed high selectivity, 305 were further analyzed by molecular dynamics simulations and free energy calculations, leading to the selection of 33 compounds for in vitro evaluation. Two orthogonal functional assays were employed: one using a small fluorogenic substrate and one following the degradation of oxytocin, a natural peptidic substrate of IRAP. In vitro evaluation suggested that several of the compounds tested can inhibit IRAP, but the inhibition profile was dependent on substrate size, consistent with the allosteric nature of the targeted site. Overall, our results describe several novel leads as IRAP inhibitors and suggest that the C-terminal domain pocket of IRAP is a promising target for developing highly selective IRAP inhibitors.

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

Cited by 11 publications

References 54 publications

The Discovery of Insulin-Regulated Aminopeptidase (IRAP) Inhibitors: A Literature Review

The Discovery of Insulin-Regulated Aminopeptidase (IRAP) Inhibitors: A Literature Review

From Angiotensin IV to Small Peptidemimetics Inhibiting Insulin-Regulated Aminopeptidase

Discovery of Selective Inhibitor Leads by Targeting an Allosteric Site in Insulin-Regulated Aminopeptidase

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