| 1. |
- Isaksson, Rebecka, et al.
(author)
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A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode
- 2019
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In: ChemistryOpen. - : Wiley. - 2191-1363. ; 8:1, s. 114-125
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Journal article (peer-reviewed)abstract
- We here report on our continued studies of ligands binding tothe promising drug target angiotensin II type 2 receptor (AT2R). Two series of compounds were synthesized and investigated. The first series explored the effects of adding small substituents to the phenyl ring of the known selective nonpeptide AT2R antagonist C38, generating small but significant shifts in AT2R affinity. One compound in the first series was equipotent to C38 and showed similar kinetic solubility, and stability in both human and mouse liver microsomes. The second series was comprised of new bicyclic derivatives, amongst which one ligand exhibited a five-fold improved affinity to AT2R ascompared to C38. The majority of the compounds in the second series, including the most potent ligand, were inferior to C38 with regard to stability in both human and mouse microsomes. In contrast to our previously reported findings, ligands with shorter carbamate alkyl chains only demonstrated slightly improved stability in microsomes. Based on data presented herein, a more adequate, tentative model of the binding modes of ligand analogues to the prototype AT2R antagonist C38 is proposed, as deduced from docking redefined by molecular dynamic simulations.
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| 2. |
- Belfrage, Anna Karin, et al.
(author)
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Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease
- 2016
-
In: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 24:12, s. 2603-2620
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Journal article (peer-reviewed)abstract
- Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors with variations in the C-terminus. Biochemical evaluation was performed using genotype 1a, both the wildtype and the drug resistant enzyme variant, R155K. Surprisingly, compounds without an acidic sulfonamide retained good inhibition, challenging our previous molecular docking model. Moreover, selected compounds in this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 protease inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance.
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| 3. |
- Wannberg, Johan, et al.
(author)
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N-(Heteroaryl)thiophene sulfonamides as angiotensin AT2 receptor ligands
- 2024
-
In: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 265
-
Journal article (peer-reviewed)abstract
- Two series of N-(heteroaryl)thiophene sulfonamides, encompassing either a methylene imidazole group or a tertbutylimidazolylacetyl group in the meta position of the benzene ring, have been synthesized. An AT(2)R selective ligand with a Ki of 42 nM was identified in the first series and in the second series, six AT(2)R selective ligands with significantly improved binding affinities and Ki values of <5 nM were discovered. The binding modes to AT(2)R were explored by docking calculations combined with molecular dynamics simulations. Although some of the high affinity ligands exhibited fair stability in human liver microsomes, comparable to that observed with C21 undergoing clinical trials, most ligands displayed a very low metabolic stability with t(1/2) of less than 10 min in human liver microsomes. The most promising ligand, with an AT(2)R K-i value of 4.9 nM and with intermediate stability in human hepatocytes (t(1/2) = 77 min) caused a concentration-dependent vasorelaxation of pre-contracted mouse aorta.
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| 4. |
- Wannberg, Johan, et al.
(author)
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N-(Methyloxycarbonyl)thiophene sulfonamides as high affinity AT2 receptor ligands
- 2021
-
In: Bioorganic & Medicinal Chemistry. - : Elsevier. - 0968-0896 .- 1464-3391. ; 29
-
Journal article (peer-reviewed)abstract
- A series of meta-substituted acetophenone derivatives, encompassing N-(alkyloxycarbonyl)thiophene sulfonamide fragments have been synthesized. Several selective AT2 receptor ligands were identified, among those a tert-butylimidazole derivative (20) with a Ki of 9.3 nM, that demonstrates a high stability in human liver microsomes (t½ = 62 min) and in human hepatocytes (t½ = 194 min). This methyloxycarbonylthiophene sulfonamide is a 20-fold more potent binder to the AT2 receptor and is considerably more stable in human liver microsomes, than a previously reported and broadly studied structurally related AT2R prototype antagonist 3 (C38). Ligand 20 acts as an AT2R agonist and caused an AT2R mediated concentration-dependent vasorelaxation of pre-contracted mouse aorta. Furthermore, in contrast to imidazole derivative C38, the tert-butylimidazole derivative 20 is a poor inhibitor of CYP3A4, CYP2D6 and CYP2C9. It is demonstrated herein that smaller alkyloxycarbonyl groups make the ligands in this series of AT2R selective compounds less prone to degradation and that a high AT2 receptor affinity can be retained after truncation of the alkyloxycarbonyl group. Binding modes of the most potent AT2R ligands were explored by docking calculations combined with molecular dynamics simulations.
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| 5. |
- Belfrage, Anna Karin, 1977-, et al.
(author)
-
Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1H)-pyrazinones
- 2015
-
In: European Journal of Organic Chemistry. - : Wiley. - 1434-193X .- 1099-0690. ; :5, s. 978-986
-
Journal article (peer-reviewed)abstract
- The development of a robust palladium-catalysed urea N-arylation protocol to install various ureas at the 3-position of the 2(1H)-pyrazinone scaffold is described. The method involves Pd(OAc)2 in combination with bidentate ligands, xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] in particular, and resulted in good to excellent coupling yields of aliphatic, aromatic, and sterically hindered ureas. Furthermore, the C-3 chlorine was shown to be selectively displaced in the presence of aryl halide ureas, and this finding was supported by density functional theory (DFT) calculations. This allows further diversification of the scaffold for the production of compound libraries. Overall, the protocol facilitates further exploitation of pyrazinones as beta-sheet-inducing scaffolds in the development of sophisticated peptidomimetics/protease inhibitors. This is exemplified here by the synthesis of a new pyrazinone-based hepatitis C virus (HCV) NS3 protease inhibitor.
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| 6. |
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| 7. |
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| 8. |
- De Rosa, Maria, et al.
(author)
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Design, synthesis and in vitro biological evaluation of oligopeptides targeting E. coli type I signal peptidase (LepB)
- 2017
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In: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 25:3, s. 897-911
-
Journal article (peer-reviewed)abstract
- Type I signal peptidases are potential targets for the development of new antibacterial agents. Here we report finding potent inhibitors of E. coli type I signal peptidase (LepB), by optimizing a previously reported hit compound, decanoyl-PTANA-CHO, through modifications at the N- and C-termini. Good improvements of inhibitory potency were obtained, with IC50s in the low nanomolar range. The best inhibitors also showed good antimicrobial activity, with MICs in the low μg/mL range for several bacterial species. The selection of resistant mutants provided strong support for LepB as the target of these compounds. The cytotoxicity and hemolytic profiles of these compounds are not optimal but the finding that minor structural changes cause the large effects on these properties suggests that there is potential for optimization in future studies.
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| 9. |
- De Rosa, Maria, et al.
(author)
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Syntheses of new tuberculosis inhibitors promoted by microwave irradiation
- 2014
-
In: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 119:2, s. 181-191
-
Research review (peer-reviewed)abstract
- Tuberculosis (TB) represents a major public health problem. The growing number of (extensively) multi-drug resistance cases indicates that there is an urgent need for discovery of new anti-TB entities, addressed towards new and specific targets, and continuous development of fast and efficient synthetic strategies to access them easily. Microwave-assisted chemistry is well suited for small-scale laboratory synthetic work, allowing full control of reaction conditions, such as temperature, pressure, and time. Microwave-assisted high-speed organic synthesis is especially useful in the lead optimization phase of drug discovery. To illustrate the advantages of modern microwave heating technology, we herein describe applications and approaches that have been useful for the synthesis of new drug-like anti-TB compounds.
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| 10. |
- Ekegren, Jenny, et al.
(author)
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Variations of the P2 Group in HIV-1 Protease Inhibitors Containing a Tertiary Alcohol in the Transition-State Mimicking Scaffold
- 2006
-
In: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 4:16, s. 3040-3043
-
Journal article (peer-reviewed)abstract
- The development of synthetic protocol leading to HIV-1 protease inhibitors with a tertiary alcohol based transition-state mimicking unit and different P2 side chains was investigated. (2S)-2-benztloxirane-2-carboxylic acid ((S)-5) was used as a key intermediate in the synthesis of the new HIV-1 protease inhibitors. (S)-5 was coupled with different amines using EDC, NMM, and HOBT, resulting in the corresponding amides at low to moderate yields. The observation supports the hypothesis that intramolecular hydrogen bonding to the tertiary alcohol in the transition-state mimic is present in these molecules. Purification by reverse-phase LC-MS resulted in moderate to good yields of most target compounds. The HIV-1 protease inhibition data suggest that the size and polarity of the P2 substituent are crucial to allow proper accommodation in the S2 sub-site.
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| 11. |
- Engen, Karin, et al.
(author)
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Inhibition of Insulin-Regulated Aminopeptidase by Imidazo[1,5-α]pyridines; Synthesis and Evaluation
- 2024
-
In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067.
-
Journal article (peer-reviewed)abstract
- Inhibition of Insulin-regulated Aminopeptidase (IRAP) has been shown to improve cognitive functions in several animal models. Recently, we performed a screening campaign identifying novel small-molecule based compounds acting as inhibitors of the enzymatic activity IRAP. Here we report on the chemical synthesis, structure-activity relationships (SAR) and initial characterization of physicochemical properties of a series of imidazo[1,5-α]pyridine-based inhibitors, including delineation of their mode of action as non-competitive inhibitors with a small L-leucine-based IRAP substrate. The best compound displays an pIC50 values of 6.0. We elucidate the importance of two chiral sites in these molecules and find they have little impact on the compound´s metabolic stability or physicochemical properties. The carbonyl group of a central urea moiety was initially believed to mimic substrate binding to a catalytically important Zn2+ ion in the active site, although the plausibility of this binding hypothesis is challenged by observation of excellent selectivity versus the closely related aminopeptidase N (APN). Taken together with the non-competitive inhibition pattern, we also consider an alternative model of allosteric binding.
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| 12. |
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| 13. |
- Frasca, Serena, et al.
(author)
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Toward Biomass-Based Organic Electronics : Continuous Flow Synthesis and Electropolymerization of N-Substituted Pyrroles
- 2024
-
In: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 9:12, s. 13852-13859
-
Journal article (peer-reviewed)abstract
- Pyrroles are foundational building blocks in a wide array of disciplines, including chemistry, pharmaceuticals, and materials science. Currently sourced from nonrenewable fossil sources, there is a strive to explore alternative and sustainable synthetic pathways to pyrroles utilizing renewable feedstocks. The utilization of biomass resources presents a compelling solution, particularly given that several key bulk and fine chemicals already originate from biomass. For instance, 2,5-dimethoxytetrahydrofuran and aniline are promising candidates for biomass-based chemical production. In this study, we present an innovative approach for synthesizing N-substituted pyrroles by modifying the Clauson-Kaas protocol, starting from 2,5-dimethoxytetrahydrofuran as the precursor. The developed methodology offers the advantage of producing pyrroles under mild reaction conditions with the potential for catalyst-free reactions depending upon the structural features of the substrate. We devised protocols suitable for both continuous flow and batch reactions, enabling the conversion of a wide range of anilines and sulfonamides into their respective N-substituted pyrroles with good to excellent yields. Moreover, we demonstrate the feasibility of depositing thin films of the corresponding polymers onto electrodes through in situ electropolymerization. This innovative application showcases the potential for sustainable, biomass-based organic electronics, thus, paving the way for environmentally friendly advancements in this field.
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| 14. |
- Frasca, Serena, et al.
(author)
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Toward biomass-based organic electronics: Continuous flow synthesis and electropolymerization of N-substituted polypyrroles
- 2023
-
In: ACS Spring meeting 2023. - Indianapolis.
-
Conference paper (peer-reviewed)abstract
- Pyrroles are important building blocks in many areas of chemistry, pharmaceuticals and materials. Pyrroles are currently fossil-based and transition to renewable alternatives demands new synthetic pathways. The use of biomass is a very attractive option for more sustainable solutions and several bulk and fine chemical are already produced from biomass. 2,5-Dimethoxytetrahydrofuran is an example of fine chemical derived from carbohydrate fraction of biomass. Here we report the synthesis of N-substituted pyrroles through a modified Clauson-Kass protocol starting from 2,5-dimethoxytetrahydrofuran. The proposed method allows to obtain pyrroles under mild reaction conditions and it can be performed catalyst-free. The protocol works both in continuous flow and under batch conditions.. A wide range of anilines and sulphonamides are transformed to corresponding N-substituted pyrroles in good to excellent yields. Conductive films are achieved through electropolymerization and they show distinct redox activity. Current efforts entail the application of the material in sensors or energy storage devices. The proposed method opens the pathway to sustainable biomass-based organic electronics.
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| 15. |
- Gising, Johan, et al.
(author)
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A straightforward microwave method for rapid synthesis of N-1, C-6 functionalized 3,5-dichloro-2(1H)-pyrazinones
- 2009
-
In: Organic and biomolecular chemistry. - 1477-0520 .- 1477-0539. ; 7:13, s. 2809-2815
-
Journal article (peer-reviewed)abstract
- A rapid and versatile one-pot, 2 * 10 min microwave protocol for the prepn. of N-1 and C-6 decorated 3,5-dichloro-2(1H)-pyrazinones, e.g., I, from the corresponding primary amines and aldehyde was developed. Comparable reaction sequences using classical conditions require about 1-2 days of heating. The alpha -aminonitrile was first generated in a Strecker reaction and thereafter cyclized under microwave heating. The microwave approach developed offers the possibility of efficiently generating and utilizing functionalized 3-amino-5-chloro-2(1H)-pyrazinone-N-1-carboxylic acids as beta -strand inducing core structures in a medicinal chem. context. To illustrate the usefulness of the method, the synthesis of two novel 2(1H)-pyrazinone-contg. Hepatitis C virus NS3 protease inhibitors, e.g., II, is reported.
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| 16. |
- Gising, Johan, 1981-, et al.
(author)
-
Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket
- 2014
-
In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 57:5, s. 1790-1801
-
Journal article (peer-reviewed)abstract
- Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1′ position. Structure–activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.
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| 17. |
- Gising, Johan, 1981-
(author)
-
Design and Synthesis of Enzyme Inhibitors Against Infectious Diseases : Targeting Hepatitis C Virus NS3 Protease and Mycobacterium tuberculosis Ribonucleotide Reductase
- 2012
-
Doctoral thesis (other academic/artistic)abstract
- Infectious diseases, including hepatitis C and tuberculosis, claim the lives of over 15 million people each year. Hepatitis C is caused by the hepatitis C virus (HCV) which infects the liver and can ultimately result in liver transplantation. HCV is very adaptive as a result of its high mutation rate. Thus, there is a potential high risk for the development of drug resistance and also a possible cross-resistance due to a structural similarity between many of the HCV NS3 protease inhibitors currently in clinical trial and on the market, that all are based on a P2-proline or a proline mimic. Thus, part of the research behind this thesis was to explore a new structural P3-P2 unit for the NS3 protease inhibitors, a 2(1H)-pyrazinone moiety. A microwave-assisted protocol was developed, and the 2(1H)-pyrazinone core was synthesized in only 2 × 10 min. A series of optimization steps resulted in several submicromolar 2(1H)-pyrazinone-containing NS3 protease inhibitors that performed well against drug-resistant NS3 protease variants. The key modifications were: exchanging the unstable carbamate P3 capping group for a stable urea functionality, transferring the P2 group from the amino acid residue to the pyrazinone ring and elongating the substituent, and using an aromatic acyl sulfonamide in the P1-P1' position.The causative agent of tuberculosis is Mycobacterium tuberculosis (Mtb), which currently infects one third of the world's population. No new TB drugs have been approved in nearly 50 years and drug resistance has been observed for all of the current first-line drugs. Because of the importance of identifying novel drug targets, the ribonucleotide reductase (RNR) enzyme was investigated. The RNR enzyme consists of two R1 and two R2 subunits and is essential for Mtb replication. Starting from hits identified in a virtual screening program, a small library of low molecular weight inhibitors of the association between the R1 and R2 subunits was designed and synthesized. The compounds with the strongest affinity for the R1 subunit of RNR were further evaluated in an orthogonal activity assay. Two RNR inhibitors with promising antimycobacterial effects were identified, which can serve as leads in the further optimization of this class of compounds.
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| 18. |
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| 19. |
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| 20. |
- GISING, Johan, et al.
(author)
-
INHIBITORS OF METALLO-BETA-LACTAMASES : WO/2018/215800
- 2018
-
Patent (pop. science, debate, etc.)abstract
- The present invention relates to certain compounds that function as inhibitors of bacterial metallo-beta-lactamases. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of a bacterial infection.
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| 21. |
- Gising, Johan, et al.
(author)
-
Microwave-assisted synthesis of anti-tuberculosis, HIV and hepatitis C agents
- 2014
-
In: Microwaves in Drug Discovery and Development. - Unitec House, 2 Albert Place, London N3 1QB, UK : Future Medicine. - 9781910419298 - 9781910419311 ; , s. 34-54
-
Book chapter (peer-reviewed)abstract
- Microwave heating technology is ideally suited to small-scale discovery chemistry applications, as it allows for full reaction control, rapid (super)heating, short reaction times, high safety and rapid feedback. These unique properties offer unparalleled opportunities for medicinal chemists to speed up the lead optimization process in early drug discovery. To illustrate these advantages, we herein describe a number of recent applications of dedicated microwave instrumentation in the synthesis of small molecules targeting three of the most prevalent infectious diseases: tuberculosis, HIV/AIDS and hepatitis C.
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| 22. |
- Gising, Johan, et al.
(author)
-
Microwave-assisted synthesis of small molecules targeting the infectious diseases tuberculosis, HIV/AIDS, malaria and hepatitis C
- 2012
-
In: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 10:14, s. 2713-2729
-
Journal article (peer-reviewed)abstract
- The unique properties of microwave in situ heating offer unparalleled opportunities for medicinal chemists to speed up lead optimisation processes in early drug discovery. The technology is ideal for small-scale discovery chemistry because it allows full reaction control, short reaction times, high safety and rapid feedback. To illustrate these advantages, we herein describe applications and approaches in the synthesis of small molecules to combat four of the most prevalent infectious diseases; tuberculosis, HIV/AIDS, malaria and hepatitis C, using dedicated microwave instrumentation.
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| 23. |
- Gising, Johan, 1981-, et al.
(author)
-
The Discovery of New Inhibitors of Insulin-Regulated Aminopeptidase by a High-Throughput Screening of 400,000 Drug-like Compounds
- 2024
-
In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 25:7
-
Journal article (peer-reviewed)abstract
- With the ambition to identify novel chemical starting points that can be further optimized into small drug-like inhibitors of insulin-regulated aminopeptidase (IRAP) and serve as potential future cognitive enhancers in the clinic, we conducted an ultra-high-throughput screening campaign of a chemically diverse compound library of approximately 400,000 drug-like small molecules. Three biochemical and one biophysical assays were developed to enable large-scale screening and hit triaging. The screening funnel, designed to be compatible with high-density microplates, was established with two enzyme inhibition assays employing either fluorescent or absorbance readouts. As IRAP is a zinc-dependent enzyme, the remaining active compounds were further evaluated in the primary assay, albeit with the addition of zinc ions. Rescreening with zinc confirmed the inhibitory activity for most compounds, emphasizing a zinc-independent mechanism of action. Additionally, target engagement was confirmed using a complementary biophysical thermal shift assay where compounds causing positive/negative thermal shifts were considered genuine binders. Triaging based on biochemical activity, target engagement, and drug-likeness resulted in the selection of 50 qualified hits, of which the IC50 of 32 compounds was below 3.5 µM. Despite hydroxamic acid dominance, diverse chemotypes with biochemical activity and target engagement were discovered, including non-hydroxamic acid compounds. The most potent compound (QHL1) was resynthesized with a confirmed inhibitory IC50 of 320 nM. Amongst these compounds, 20 new compound structure classes were identified, providing many new starting points for the development of unique IRAP inhibitors. Detailed characterization and optimization of lead compounds, considering both hydroxamic acids and other diverse structures, are in progress for further exploration.
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| 24. |
- Gising, Johan, et al.
(author)
-
Trisubstituted Imidazoles as Mycobacterium tuberculosis Glutamine Synthetase Inhibitors
- 2012
-
In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:6, s. 2894-2898
-
Journal article (peer-reviewed)abstract
- Mycobacterium tuberculosis glutamine synthetase (MtGS) is a promising target for antituberculosis drug discovery. In a recent high-throughput screening study we identified several classes of MtGS inhibitors targeting the ATP-binding site. We now explore one of these classes, the 2-tert-butyl-4,5-diarylimidazoles, and present the design, synthesis, and X-ray crystallographic studies leading to the identification of MtGS inhibitors with submicromolar IC(50) values and promising antituberculosis MIC values.
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| 25. |
- Lazorova, Lucia, et al.
(author)
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Structural Features Determining the Intestinal Epithelial Permeability and Efflux of Novel HIV-1 Protease Inhibitors
- 2011
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In: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 100:9, s. 3763-3772
-
Journal article (peer-reviewed)abstract
- The primary aim of this study was to identify structural features that alter the intestinal epithelial permeability and efflux in a series of novel HIV-1 protease inhibitors (PIs). Eleven PIs were selected containing a tertiary alcohol in a transition-state mimicking scaffold, in which two substituents (R1 and R2) were varied systematically. Indinavir was selected as a reference compound. The apical-to-basolateral permeability was investigated in 2/4/A1 and Caco-2 monolayers. In addition, the basolateral-to-apical permeability was investigated in the Caco-2 monolayers and the efflux ratios were calculated. The absence of active drug transport processes in 2/4/A1 cells allowed identification and modeling of structural elements affecting the passive permeability. For instance, small aromatic R1 substituents and a small (bromo-) R2 substituent were associated with a high passive permeability. Efflux studies in Caco-2 cells indicated that amide-substituted neutral hydrophobic amino acids, such as valine and leucine, in the R1 position, reduced the apical-to-basolateral transport and enhanced the efflux. We conclude that our investigation revealed structural features that alter the intestinal epithelial permeability and efflux in the series of PIs and hope that these results can contribute to the synthesis of PIs with improved permeability and limited efflux properties.
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| 26. |
- Lindman, Jens, et al.
(author)
-
Diastereoselective Synthesis of N-Methylspiroindolines by Intramolecular Mizoroki–Heck Annulations
- 2022
-
In: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 7:36
-
Journal article (peer-reviewed)abstract
- Spiroindolines represent a privileged structure in medicinal chemistry, although stereocontrol around the spirocarbon can be a synthetic challenge. Here we present a palladium(0)-catalyzed intramolecular Mizoroki–Heck annulation reaction from (+)-Vince lactam-derived cyclopentenyl-tethered 2-bromo-N-methylanilines for the formation of N-methylspiroindolines. A series of 14 N-methylspiroindolines were synthesized in 59–81% yield with diastereoselectivity >98%, which was rationalized by density functional theory calculations and confirmed through X-ray crystallography. One spiroindoline was converted to an N- and C-terminal protected rigidified unnatural amino acid, which could be orthogonally deprotected.
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| 27. |
- Lindman, Jens, 1990-
(author)
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Palladium(0)-Catalyzed Spirocyclization and Carbonylation Reactions : Ligands Targeting the Angiotensin II Type 2 Receptor
- 2023
-
Doctoral thesis (other academic/artistic)abstract
- Palladium(0)-catalyzed chemistry represents one of the most important methods for the construction of carbon-carbon bonds, which are ubiquitous in organic compounds. The first part of this thesis describes the palladium(0)-catalyzed diastereoselective Mizoroki-Heck reaction of Vince lactam-derived precursors for the formation of spiroindolines (paper I) and spirooxindoles, which are scaffolds present in several natural products with interesting biological activity. The scope of the spiroindoline synthesis was investigated by varying the substitution on the cyclopentenyl-tethered aniline spirocyclization precursor. The mechanistic reasons behind the high diastereoselectivity of the spirocyclization reaction was also investigated through density functional theory (DFT) calculations. Functionalization of the N-terminal amino acid of therapeutic peptides is a strategy that has been employed for the improvement of metabolic stability. In paper II, a palladium(0)-catalyzed carbonylation method employing ex situ carbon monoxide generation from Mo(CO)6 in a two-chamber system is used for the N-capping of amino acids using various aryl bromides and triflates. The second part of the thesis describes the synthesis and biological evaluation of angiotensin II type 2 receptor (AT2R) ligands. The AT2R is a G-protein coupled receptor belonging to the renin-angiotensin-aldosterone system (RAAS), which is most commonly associated with the hypertensive disorder caused by an exaggerated activation of the angiotensin II type 1 receptor (AT1R). However, activation of AT2R exerts different and sometimes completely opposing effects to AT1R and has been implicated in processes related to neuropathic pain, where the AT2R antagonist EMA401 has been in clinical trials for this indication. In papers III and IV, the AT2R antagonist C38 developed in our laboratory, is used as a model compound for the synthesis of analogs with the aim of expanding our knowledge regarding the structure-activity relationship of the C38 scaffold. Three general strategies were used; functionalization of the C38 phenyl ring, replacement of the benzyl imidazole of C38 with bicyclic amides and extension of the linker between the phenyl ring and imidazole by the inclusion of a carbonyl. Through these approaches, compounds with improved affinity towards AT2R and increased metabolic stability were identified, which might serve as tools for the continued study of the AT2R.
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| 28. |
- Lindman, Jens, 1990-, et al.
(author)
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Two-chamber Aminocarbonylation of Aryl Bromides and Triflates Using Amino Acids as Nucleophiles
- 2023
-
In: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 88:18, s. 12978-12985
-
Journal article (peer-reviewed)abstract
- A palladium(0)-catalyzed aminocarbonylation reaction employing molybdenum hexacarbonyl as a carbon monoxide precursor for the production of N-capped amino acids using aryl and heteroaryl bromides and triflates is reported. The carbon monoxide is formed ex situ through the use of a two-chamber system, where carbon monoxide generated in one chamber is free to diffuse over and be consumed in the other palladium-catalyzed reaction chamber. Using this method, two series of aryl bromides and aryl triflates were utilized to synthesize 21 N-capped amino acids in isolated yields between 40 and 91%.
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| 29. |
- Nordqvist, Anneli, et al.
(author)
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Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]-pyridine based Mycobacterium tuberculosis glutamine synthetase inhibitors
- 2012
-
In: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 3:5, s. 620-626
-
Journal article (peer-reviewed)abstract
- Based on an imidazo[1,2-a]pyridine hit from a high-throughput screen directed at the M. tuberculosis enzyme glutamine synthetase, a hit expansion was performed by synthesizing a series of analogs. A set of 16 molecules was first synthesized according to a statistical molecular design approach. One potent inhibitor was identified (IC50 = 3.0 µM), which led to the synthesis of 17 additional imidazo[1,2-a]pyridines in a follow-up study. Among these, several inhibitors were identified showing single digit micromolar potency. An X-ray structure of one of these revealed the binding mode of this class of inhibitors in the ATP-binding site, and allowed us to rationalize some of the structure-activity relationships observed.
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| 30. |
- Odell, Luke R., et al.
(author)
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Functionalized 3-amino-imidazo[1,2-a]pyridines : A novel class of drug-like Mycobacterium tuberculosis glutamine synthetase inhibitors
- 2009
-
In: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 19:16, s. 4790-4793
-
Journal article (peer-reviewed)abstract
- 3-Amino-imidazo[1,2-a]pyridines have been identified as a novel class of Mycobacterium tuberculosis glutamine synthetase inhibitors. Moreover, these compounds represent the first drug-like inhibitors of this enzyme. A series of compounds exploring structural diversity in the pyridine and phenyl rings have been synthesized and biologically evaluated. Compound 4n was found to be the most potent inhibitor (IC50 = 0.38 ± 0.02 μM). This compound was significantly more potent than the known inhibitors, L-methionine-SR-sulfoximine and phosphinothricin.
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| 31. |
- Olliver, Marie, et al.
(author)
-
ENABLE : an engine for European antibacterial drug discovery and development
- 2021
-
In: Nature reviews. Drug discovery. - : Springer Nature. - 1474-1776 .- 1474-1784. ; 20:6, s. 407-408
-
Journal article (other academic/artistic)abstract
- ENABLE is an antibacterial drug discovery and development consortium formed as a publicprivate partnership in 2014 as part of the Innovative Medicines Initiative (IMI) New Drugs for Bad Bugs (ND4BB) programme. With the project soon ending, here we provide a brief overview and reflect on its achievements, strengths and weaknesses.
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| 32. |
- Roy, Tamal, et al.
(author)
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2-Alkyl substituted benzimidazoles as a new class of selective AT2 receptor ligands
- 2022
-
In: Bioorganic & Medicinal Chemistry. - : Elsevier. - 0968-0896 .- 1464-3391. ; 66
-
Journal article (peer-reviewed)abstract
- Ligands comprising a benzimidazole rather than the imidazole ring that is common in AT2R ligands e.g. in the AT2R agonist C21, can provide both high affinity and receptor selectivity. In particular, compounds encompassing benzimidazoles, substituted in the 2-position with small bulky groups such as an isopropyl (Ki = 4.0 nM) or a tert-butyl (Ki = 5.3 nM) or alternatively a thiazole heterocycle (Ki = 5.1 nM) demonstrate high affinity and AT2R selectivity. An n-butyl chain, as found in the AT1R selective sartans, makes the ligand less receptor selective. The isobutyl group on the biaryl scaffold present in most AT2R selective ligands reported so far was originally derived from the nonselective potent AT1R/AT2R ligand L-162,313. Notably, in all ligands discussed herein, the isobutyl group was substituted by an n-propyl group and ligands with high affinity to AT2R were provided and in addition the majority of them demonstrate a favorable AT2R/AT1R selectivity. The introduction of fluoro atoms in various positions had no pronounced effect on the affinity data. Ligands with a thiazole or a tert-butyl group attached to the 2-position and with a terminal trifluoromethyl butoxycarbonyl sidechain exhibited a similar stability as C21 in human liver microsomes, while other ligands examined were less stable in the microsome assay.
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| 33. |
- Russo, Francesco, et al.
(author)
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Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents
- 2015
-
In: ChemistryOpen. - : Wiley. - 2191-1363. ; 4:3, s. 342-362
-
Journal article (peer-reviewed)abstract
- This is the first report of 5-styryl-oxathiazol-2-ones as inhibitors of the Mycobacterium tuberculosis (Mtb) proteasome. As part of the study, the structure-activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated. Furthermore, the prepared compounds displayed a good selectivity profile for Mtb compared to the human proteasome. The 5-styryl-oxathiazol-2-one inhibitors identified showed little activity against replicating Mtb, but were rapidly bactericidal against nonreplicating bacteria. (E)-5-(4-Chlorostyryl)-1,3,4-oxathiazol-2-one) was most effective, reducing the colony-forming units (CFU)/mL below the detection limit in only seven days at all concentrations tested. The results suggest that this new class of Mtb proteasome inhibitors has the potential to be further developed into novel antitubercular agents for synergistic combination therapies with existing drugs.
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| 34. |
- Stam, Frida, et al.
(author)
-
Hydrogen Peroxide Induced Toxicity Is Reversed by the Macrocyclic IRAP-Inhibitor HA08 in Primary Hippocampal Cell Cultures
- 2022
-
In: Current Issues in Molecular Biology. - : MDPI. - 1467-3037 .- 1467-3045. ; 44:10, s. 5000-5012
-
Journal article (peer-reviewed)abstract
- Angiotensin IV (Ang IV), a metabolite of Angiotensin II, is a bioactive hexapeptide that inhibits the insulin-regulated aminopeptidase (IRAP). This transmembrane zinc metallopeptidase with many biological functions has in recent years emerged as a new pharmacological target. IRAP is expressed in a variety of tissues and can be found in high density in the hippocampus and neocortex, brain regions associated with cognition. Ang IV is known to improve memory tasks in experimental animals. One of the most potent IRAP inhibitors known today is the macrocyclic compound HA08 that is significantly more stable than the endogenous Ang IV. HA08 combines structural elements from Ang IV and the physiological substrates oxytocin and vasopressin, and binds to the catalytic site of IRAP. In the present study we evaluate whether HA08 can restore cell viability in rat primary cells submitted to hydrogen peroxide damage. After damaging the cells with hydrogen peroxide and subsequently treating them with HA08, the conceivable restoring effects of the IRAP inhibitor were assessed. The cellular viability was determined by measuring mitochondrial activity and lactate dehydrogenase (LDH) release. The mitochondrial activity was significantly higher in primary hippocampal cells, whereas the amount of LDH was unaffected. We conclude that the cell viability can be restored in this cell type by blocking IRAP with the potent macrocyclic inhibitor HA08, although the mechanism by which HA08 exerts its effects remains unclear.
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| 35. |
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| 36. |
- Sävmarker, Jonas, 1979-, et al.
(author)
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Direct Palladium(II)-Catalyzed Synthesis of Arylamidines from Aryltrifluoroborates
- 2012
-
In: Organic Letters. - : American Chemical Society (ACS). - 1523-7060 .- 1523-7052. ; 14:9, s. 2394-2397
-
Journal article (peer-reviewed)abstract
- A fast and convenient synthesis of arylamidines starting from readily available potassium aryltrifluoroborates and cyanamides is reported. The coupling was achieved by Pd(II)-catalysis in a one step 20 min microwave protocol using Pd(O2CCF3), 6-methyl-2,2'-bipyridyl, TFA, and MeOH, providing the corresponding arylamidines in moderate to excellent yields.
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| 37. |
- Zelleroth, Sofia, 1990-, et al.
(author)
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The decanoate esters of nandrolone, testosterone, and trenbolone induce steroid specific memory impairment and somatic effects in the male rat
- 2024
-
In: Hormones and Behavior. - : Elsevier. - 0018-506X .- 1095-6867. ; 161
-
Journal article (peer-reviewed)abstract
- Long-term use of anabolic androgenic steroids (AAS) in supratherapeutic doses is associated with severe adverse effects, including physical, mental, and behavioral alterations. When used for recreational purposes several AAS are often combined, and in scientific studies of the physiological impact of AAS either a single compound or a cocktail of several steroids is often used. Because of this, steroid-specific effects have been difficult to define and are not fully elucidated. The present study used male Wistar rats to evaluate potential somatic and behavioral effects of three different AAS; the decanoate esters of nandrolone, testosterone, and trenbolone. The rats were exposed to 15 mg/kg of nandrolone decanoate, testosterone decanoate, or trenbolone decanoate every third day for 24 days. Body weight gain and organ weights (thymus, liver, kidney, testis, and heart) were measured together with the corticosterone plasma levels. Behavioral effects were studied in the novel object recognition-test (NOR-test) and the multivariate concentric square field-test (MCSF-test). The results conclude that nandrolone decanoate, but neither testosterone decanoate nor trenbolone decanoate, caused impaired recognition memory in the NOR-test, indicating an altered cognitive function. The behavioral profile and stress hormone level of the rats were not affected by the AAS treatments. Furthermore, the study revealed diverse AAS-induced somatic effects i.e., reduced body weight development and changes in organ weights. Of the three AAS included in the study, nandrolone decanoate was identified to cause the most prominent impact on the male rat, as it affected body weight development, the weights of multiple organs, and caused an impaired memory function.
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| 38. |
- Örtqvist, Pernilla, et al.
(author)
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Discovery of Achiral Inhibitors of the Hepatitis C Virus NS3 Protease based on 2(1H)-pyrazinones
- 2010
-
In: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 18:17, s. 6512-6525
-
Journal article (peer-reviewed)abstract
- Herein, the design, synthesis and inhibitory potency of a series of novel hepatitis C virus (HCV) NS3 protease inhibitors are presented. These inhibitors are based on a 2(1H)-pyrazinone P3 scaffold in combination with either a P2 phenylglycine or a glycine, and they were evaluated on the wild type as well as on two resistant variants of the enzyme, A156T and D168V. Molecular modelling suggested that the aromatic side-chain of the P2 phenylglycine occupies the same space as the substituent in position 6 on the pyrazinone core. The versatile synthetic route applied for the pyrazinone synthesis made a switch between the two positions easily feasible, resulting in phenyl- or benzyl substituted pyrazinones and leaving glycine as the P2 residue. Of several P1-P1′ residues evaluated, an aromatic P1-P1′ scaffold was found superior in combination with the new P3-P2 building block. As a result, an entirely new type of achiral and rigidified inhibitors was discovered, with the best of the novel inhibitors having fourfold improved potency compared to the corresponding tripeptide lead. We consider these achiral inhibitors highly suitable as starting points for further optimization.
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