| 1. |
- Borhade, Sanjay R, et al.
(författare)
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Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Arylsulfonamides
- 2014
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Ingår i: ChemistryOpen. - : Wiley. - 2191-1363. ; 3:6, s. 256-263
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Tidskriftsartikel (refereegranskat)abstract
- The inhibition of insulin-regulated aminopeptidase (IRAP, EC 3.4.11.3) by angiotenesin IV is known to improve memory and learning in rats. Screening 10 500 low-molecular-weight compounds in an enzyme inhibition assay with IRAP from Chinese Hamster Ovary (CHO) cells provided an arylsulfonamide (N-(3-(1H-tetrazol-5-yl)phenyl)-4-bromo-5-chlorothiophene-2-sulfonamide), comprising a tetrazole in the meta position of the aromatic ring, as a hit. Analogues of this hit were synthesized, and their inhibitory capacities were determined. A small structure-activity relationship study revealed that the sulfonamide function and the tetrazole ring are crucial for IRAP inhibition. The inhibitors exhibited a moderate inhibitory potency with an IC50=1.1±0.5 μm for the best inhibitor in the series. Further optimization of this new class of IRAP inhibitors is required to make them attractive as research tools and as potential cognitive enhancers.
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| 2. |
- Engen, Karin, et al.
(författare)
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Identification of Drug-Like Inhibitors of Insulin-Regulated Aminopeptidase Through Small-Molecule Screening
- 2016
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Ingår i: Assay and drug development technologies. - : Mary Ann Liebert Inc. - 1540-658X .- 1557-8127. ; 14:3, s. 180-193
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Tidskriftsartikel (refereegranskat)abstract
- Intracerebroventricular injection of angiotensin IV, a ligand of insulin-regulated aminopeptidase (IRAP), has been shown to improve cognitive functions in several animal models. Consequently, IRAP is considered a potential target for treatment of cognitive disorders. To identify nonpeptidic IRAP inhibitors, we adapted an established enzymatic assay based on membrane preparations from Chinese hamster ovary cells and a synthetic peptide-like substrate for high-throughput screening purposes. The 384-well microplate-based absorbance assay was used to screen a diverse set of 10,500 compounds for their inhibitory capacity of IRAP. The assay performance was robust with Z-values ranging from 0.81 to 0.91, and the screen resulted in 23 compounds that displayed greater than 60% inhibition at a compound concentration of 10M. After hit confirmation experiments, purity analysis, and promiscuity investigations, three structurally different compounds were considered particularly interesting as starting points for the development of small-molecule-based IRAP inhibitors. After resynthesis, all three compounds confirmed low M activity and were shown to be rapidly reversible. Additional characterization included activity in a fluorescence-based orthogonal assay and in the presence of a nonionic detergent and a reducing agent, respectively. Importantly, the characterized compounds also showed inhibition of the human ortholog, prompting our further interest in these novel IRAP inhibitors.
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| 3. |
- 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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| 4. |
- Engen, Karin, et al.
(författare)
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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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| 5. |
- Konda, Vivek, et al.
(författare)
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Safe Palladium-Catalyzed Cross-Couplings with Microwave Heating Using Continuous-Flow Silicon Carbide Reactors
- 2014
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Ingår i: Organic Process Research & Development. - : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 18:11, s. 1413-1418
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Tidskriftsartikel (refereegranskat)abstract
- Herein we present a 200 mm × 3 mm Øi silicon carbide (SiC) tube reactor for use in a commercially available microwave heated continuous-flow system. The SiC flow reactor enables palladium(0)-catalyzed reactions that, due to precipitation and subsequent hot spot formation, often followed by reactor failure, are unsuitable to conduct in standard microwave-transparent borosilicate glass reactors. We report continuous-flow protocols for the Mizoroki–Heck reaction (10 examples, 81–86% yield) as well as the Suzuki–Miyaura cross-coupling (14 examples, 70–87% yield), showing the utility of the SiC reactor. Furthermore, we performed a scale-out of the NSAID biphenylacetic acid, achieving outputs of 14 mmol/h of the Suzuki–Miyaura reaction, and a 72% overall yield over three steps. The SiC reactor enabled fast and efficient temperature control, high robustness, and easy maintenance.
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| 6. |
- Lu, Lu, 1984-, et al.
(författare)
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Synthesis and in vitro biological evaluation of quinolinyl pyrimidines targeting type II NADH-dehydrogenase (NDH-2)
- 2022
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Ingår i: ACS - Infectious Diseases. - : American Chemical Society (ACS). - 2373-8227. ; 8:3, s. 482-498
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Tidskriftsartikel (refereegranskat)abstract
- Type II NADH dehydrogenase (NDH-2) is an essential component of electron transfer in many microbial pathogens but has remained largely unexplored as a potential drug target. Previously, quinolinyl pyrimidines were shown to inhibit Mycobacterium tuberculosis NDH-2, as well as the growth of the bacteria [Shirude, P. S.; ACS Med. Chem. Lett. 2012, 3, 736−740]. Here, we synthesized a number of novel quinolinyl pyrimidines and investigated their properties. In terms of inhibition of the NDH-2 enzymes from M. tuberculosis and Mycobacterium smegmatis, the best compounds were of similar potency to previously reported inhibitors of the same class (half-maximal inhibitory concentration (IC50) values in the low-μM range). However, a number of the compounds had much better activity against Gram-negative pathogens, with minimum inhibitory concentrations (MICs) as low as 2 μg/mL. Multivariate analyses (partial least-squares (PLS) and principle component analysis (PCA)) showed that overall ligand charge was one of the most important factors in determining antibacterial activity, with patterns that varied depending on the particular bacterial species. In some cases (e.g., mycobacteria), there was a clear correlation between the IC50 values and the observed MICs, while in other instances, no such correlation was evident. When tested against a panel of protozoan parasites, the compounds failed to show activity that was not linked to cytotoxicity. Further, a strong correlation between hydrophobicity (estimated as clog P) and cytotoxicity was revealed; more hydrophobic analogues were more cytotoxic. By contrast, antibacterial MIC values and cytotoxicity were not well correlated, suggesting that the quinolinyl pyrimidines can be optimized further as antimicrobial agents.
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| 7. |
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