المؤلفون: Leino, Teppo O., Noutsias, Dimitris, Helttunen, Kaisa, Moilanen, Jani O., Tarkkonen, Eeki, Kalenius, Elina, Kiesilä, Anniina, Pihko, Petri M.

المصدر: European Journal of Organic Chemistry ; ISSN 1434-193X 1099-0690

الوصف: Conformationally flexible tertiary amine – thiourea−urea catalysts 1 and 2 for the Mannich reaction between imines and malonate esters are efficiently inhibited by quaternary ammonium halides. NMR titrations, isothermal titration calorimetry (ITC) and NOE experiments showed that the catalysts bind chloride and bromide ions with relatively high affinities ( K =10 3 –10 5 M −1 in acetonitrile). The halide ions not only block the active site of the catalysts, but they also induce refolding into catalytically inactive conformations upon complexation in an allosteric‐like event. At substoichiometric inhibitor:catalyst ratios, the catalysts displayed hypersensitivity to the inhibitors, with overall rates that were lower than those expected from simple 1 st order kinetics and 1 : 1 inhibitor:catalyst stoichiometry. To rationalize the observed hypersensitivity, different kinetic scenarios were examined. For catalyst 2 and the Takemoto catalyst ( 6 ), the data is consistent with 2 nd order dependency on catalyst concentration, suggesting that a mechanism involving only a single catalyst in the catalytic cycle is not operative. For catalyst 1 , an alternative scenario involving 1 st order in catalyst and catalyst poisoning at low concentrations of 1 could also rationalize the hypersensitivity. Interestingly, inhibition of catalysts 1 and 2 by halide salts led to significant loss of enantioselectivity, in contrast to the Takemoto catalyst 6 which was inhibited but with essentially no change in enantioselectivity.

الإتاحة: https://doi.org/10.1002/ejoc.202400321Test

المؤلفون: Leino, Teppo O., Turku, Ainoleena, Urvas, Lauri, Adhikari, Karuna, Oksanen, Jouni, Steynen, Yana, Yli-Kauhaluoma, Jari, Xhaard, Henri, Kukkonen, Jyrki P., Wallén, Erik A. A.

المساهمون: Divisions of Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Pharmaceutical Design and Discovery group, Veterinary Biosciences, Faculty of Veterinary Medicine, Faculty of Pharmacy, Department of Pharmacology, Jari Yli-Kauhaluoma / Principal Investigator, Computational Adme, Henri Xhaard / Principal Investigator, Division of Pharmaceutical Biosciences, Erik Wallen / Principal Investigator, Medicinal Chemistry research group

مصطلحات موضوعية: Agonist, Azulene, Medicinal chemistry, Orexin receptor, Sulfonamides, 3111 Biomedicine, 1182 Biochemistry, cell and molecular biology, 317 Pharmacy

الوصف: Azulene is a rare ring structure in drugs, and we investigated whether it could be used as a biphenyl mimetic in known orexin receptor agonist Nag 26, which is binding to both orexin receptors OX1 and OX2 with preference towards OX2. The most potent azulene-based compound was identified as an OX1 orexin receptor agonist (pEC50 = 5.79 +/- 0.07, maximum response = 81 +/- 8% (s.e.m. of five independent experiments) of the maximum response to orexin-A in Ca2+ elevation assay). However, the azulene ring and the biphenyl scaffold are not identical in their spatial shape and electron distribution, and their derivatives may adopt different binding modes in the binding site. ; Peer reviewed

وصف الملف: application/pdf

العلاقة: Leino , T O , Turku , A , Urvas , L , Adhikari , K , Oksanen , J , Steynen , Y , Yli-Kauhaluoma , J , Xhaard , H , Kukkonen , J P & Wallén , E A A 2023 , ' Azulene as a biphenyl mimetic in orexin/hypocretin receptor agonists ' , Bioorganic & Medicinal Chemistry , vol. 88-89 , 117325 . https://doi.org/10.1016/j.bmc.2023.117325Test; ORCID: /0000-0002-6989-1564/work/137437590; ORCID: /0000-0003-0370-7653/work/137437764; ORCID: /0000-0003-0959-7221/work/137438818; ORCID: /0000-0003-2582-7971/work/137440251; http://hdl.handle.net/10138/359559Test; c9572f10-7a1b-42fd-9f32-fe162591a425; 001001557400001

الإتاحة: http://hdl.handle.net/10138/359559Test

المؤلفون: Kilpelainen, Tommi P., Patsi, Henri T., Svarcbahs, Reinis, Julku, Ulrika H., Eteläinen, Tony S., Cui, Hengjing, Auno, Samuli, Sipari, Nina, Norrbacka, Susanna, Leino, Teppo O., Jäntti, Maria, Myöhänen, Timo T., Wallen, Erik A. A.

المساهمون: Divisions of Faculty of Pharmacy, PREP in neurodegenerative disorders, Division of Pharmaceutical Chemistry and Technology, Division of Pharmacology and Pharmacotherapy, Organismal and Evolutionary Biology Research Programme, Faculty of Pharmacy, Pharmaceutical Design and Discovery group, Drug Research Program, Erik Wallen / Principal Investigator, Medicinal Chemistry research group

مصطلحات موضوعية: Endopeptidase inhibitor, Efficient synthesis, Overexpression, Autophagy, Kyp-2047, Drug, Pharmacokinetics, Phosphorylation, Aggregation, Activation, 317 Pharmacy

الوصف: Prolyl oligopeptidase (PREP) is a widely distributedserine proteasein the human body cleaving proline-containing peptides; however, recentstudies suggest that its effects on pathogenic processes underlyingneurodegeneration are derived from direct protein-protein interactions(PPIs) and not from its regulation of certain neuropeptide levels.We discovered novel nonpeptidic oxazole-based PREP inhibitors, whichdeviate from the known structure-activity relationship forPREP inhibitors. These new compounds are effective modulators of thePPIs of PREP, reducing alpha-synuclein (alpha Syn) dimerizationand enhancing protein phosphatase 2A activity in a concentration-responsemanner, as well as reducing reactive oxygen species production. Fromthe best performing oxazoles, HUP-55 was selected for in vivo studies. Its brain penetration was evaluated, andit was tested in alpha Syn virus vector-based and alpha Syn transgenicmouse models of Parkinson's disease, where it restored motorimpairment and reduced levels of oligomerized alpha Syn in the striatumand substantia nigra. ; Peer reviewed

وصف الملف: application/pdf

العلاقة: Kilpelainen , T P , Patsi , H T , Svarcbahs , R , Julku , U H , Eteläinen , T S , Cui , H , Auno , S , Sipari , N , Norrbacka , S , Leino , T O , Jäntti , M , Myöhänen , T T & Wallen , E A A 2023 , ' Nonpeptidic Oxazole-Based Prolyl Oligopeptidase Ligands with Disease-Modifying Effects on alpha-Synuclein Mouse Models of Parkinson's Disease ' , Journal of Medicinal Chemistry , vol. 66 , no. 11 , pp. 7475-7496 . https://doi.org/10.1021/acs.jmedchem.3c00235Test; ORCID: /0000-0002-0786-2493/work/137858078; ORCID: /0000-0002-9277-6687/work/137863336; ORCID: /0000-0003-2582-7971/work/137863726; ORCID: /0000-0002-1312-9837/work/137864347; ORCID: /0000-0003-2931-6853/work/137864976; ORCID: /0000-0003-0802-2557/work/137865122; http://hdl.handle.net/10138/563197Test; 16a1b13f-44d5-4dbb-b1f4-a84fa0485c6f; 001005897700001

الإتاحة: http://hdl.handle.net/10138/563197Test

المؤلفون: Kilpeläinen, Tommi P., Pätsi, Henri T., Svarcbahs, Reinis, Julku, Ulrika H., Eteläinen, Tony S., Cui, Hengjing, Auno, Samuli, Sipari, Nina, Norrbacka, Susanna, Leino, Teppo O., Jäntti, Maria, Myöhänen, Timo T., Wallén, Erik A. A.

المساهمون: Terveyden Tutkimuksen Toimikunta, Helsinki Institute of Life Science, Helsingin Yliopisto, Business Finland, Sigrid Juselius Foundation

المصدر: Journal of Medicinal Chemistry ; volume 66, issue 11, page 7475-7496 ; ISSN 0022-2623 1520-4804

الإتاحة: https://doi.org/10.1021/acs.jmedchem.3c00235Test

المؤلفون: Leino, Teppo O., Sieger, Peter, Yli-Kauhaluoma, Jari, Wallén, Erik A.A., Kley, Jörg T.

مصطلحات موضوعية: Indole, Naphthalene, Photostability, Scaffold hopping, atsuleeni, lääkesuunnittelu, aromaattiset yhdisteet, lääkekemia, biologinen aktiivisuus

الوصف: Azulene is a bicyclic scaffold rarely applied in medicinal chemistry. Here we report physicochemical and in vitro parameters relevant for drug discovery for a series of diversely substituted azulenes. We synthesized and characterized several scaffold hopping series of analogously substituted azulenes, indoles and naphthalenes. This enabled a comparison of azulene with the more common scaffolds indole and naphthalene. Our data indicates that undesirably low photostability of azulenes is restricted to certain substitution patterns. Generally, we conclude that azulene is an underused lipophilic bicycle and should be considered as a valuable complement to the collection of medicinal chemistry scaffolds. ; peerReviewed

وصف الملف: application/pdf; fulltext

العلاقة: European Journal of Medicinal Chemistry; 237; 330800; Research Council of Finland; Suomen Akatemia; Leino, T. O., Sieger, P., Yli-Kauhaluoma, J., Wallén, E. A., & Kley, J. T. (2022). The azulene scaffold from a medicinal chemist's perspective : Physicochemical and in vitro parameters relevant for drug discovery. European Journal of Medicinal Chemistry , 237 , Article 114374. https://doi.org/10.1016/j.ejmech.2022.114374Test; CONVID_118852176; URN:NBN:fi:jyu-202204262374; http://urn.fi/URN:NBN:fi:jyu-202204262374Test

الإتاحة: http://urn.fi/URN:NBN:fi:jyu-202204262374Test

المؤلفون: Leino, Teppo O., Turku, Ainoleena, Yli-Kauhaluoma, Jari Tapani, Kukkonen, Jyrki P., Xhaard, Henri, Wallén, Erik A. A.

المساهمون: Faculty of Pharmacy, Pharmaceutical Design and Discovery group, Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Jari Yli-Kauhaluoma / Principal Investigator, Jyrki Kukkonen / Principal Investigator, Veterinary Biochemistry and Cell Biology, Veterinary Biosciences, Departments of Faculty of Veterinary Medicine, Faculty of Veterinary Medicine, Department of Physiology, Medicum, Henri Xhaard / Principal Investigator, Erik Wallen / Principal Investigator, Medicinal Chemistry research group

مصطلحات موضوعية: 317 Pharmacy, 116 Chemical sciences, Azulene, Orexin receptor, Potentiator, Agonist, Antagonist, Sleep-wake regulation, PROTEIN-COUPLED RECEPTORS, HAMSTER OVARY CELLS, SIGNAL-TRANSDUCTION, CA2+ INFLUX, OX1, DERIVATIVES, INHIBITORS, PEPTIDES, LIGANDS, KINASE

الوصف: A library of 70 000 synthetically accessible azulene-based compounds was virtually screened at the OX2 receptor. Based on the results, a series of azulene derivatives was synthesized and the binding to and activation of both orexin receptor subtypes were assessed. Two most promising binders were determined to have inhibition constants in the 3-9 mu M range and two other compounds showed weak OX2 receptor agonism. Furthermore, three compounds exhibited a concentration-dependent potentiation of the response to orexin-A at the OX1 but not the OX2 receptors. Altogether this data opens new approaches for further development of antagonists, agonists, and potentiators of orexin response based on the azulene scaffold. (C) 2018 Elsevier Masson SAS. All rights reserved. ; Peer reviewed

وصف الملف: application/pdf

العلاقة: Leino , T O , Turku , A , Yli-Kauhaluoma , J T , Kukkonen , J P , Xhaard , H & Wallén , E A A 2018 , ' Azulene-based compounds for targeting orexin receptors ' , European Journal of Medicinal Chemistry , vol. 157 , pp. 88-100 . https://doi.org/10.1016/j.ejmech.2018.07.040Test; ORCID: /0000-0003-0370-7653/work/50286680; ORCID: /0000-0003-0959-7221/work/50289879; ORCID: /0000-0003-2582-7971/work/50290708; ORCID: /0000-0002-6989-1564/work/63349244; http://hdl.handle.net/10138/319069Test; be64b9c4-f27c-4b99-9902-88569234386b; 85050849346; 000447480000008

الإتاحة: http://hdl.handle.net/10138/319069Test

المؤلفون: Rinne, Maiju K., Leino, Teppo O., Turku, Ainoleena, Turunen, Pauli M., Steynen, Yana, Xhaard, Henri, Wallen, Erik A. A., Kukkonen, Jyrki P.

المساهمون: Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, Veterinary Biosciences, Departments of Faculty of Veterinary Medicine, Pharmaceutical Design and Discovery group, Medicum, Department of Physiology, Veterinary Biochemistry and Cell Biology, Henri Xhaard / Principal Investigator, Computational Adme, Drug Research Program, Erik Wallen / Principal Investigator, Jyrki Kukkonen / Principal Investigator, Medicinal Chemistry research group

مصطلحات موضوعية: Orexin, Calcium, Phospholipase C, cAMP, Cell death, ERK, ACTIVATED PROTEIN-KINASE, OREXIN TYPE-2 RECEPTOR, HAMSTER OVARY CELLS, OX1 RECEPTOR, NARCOLEPSY, SLEEP, MICE, WAKEFULNESS, APOPTOSIS, GENE, 317 Pharmacy

الوصف: One promising series of small-molecule orexin receptor agonists has been described, but the molecular pharmacological properties, i.e. ability and potency to activate the different orexin receptor-regulated signal pathways have not been reported for any of these ligands. We have thus here assessed these properties for the most potent ligand of the series, 4'-methoxy-N,N-dimethyl-3'4N-(3-{[2-(3-methylbenzamido)ethyl]amino}phenyl sulfamoy1]-(1,1'-biphenyl)-3-carboxamide (Nag 26). Chinese hamster ovary-K1 cells expressing human orexin receptor subtypes OX1 and OX2 were used. Ca2+ elevation and cell viability and death were assessed by fluorescent methods, the extracellular signal-regulated kinase pathway by a luminescent Elk-1 reporter assay, and phospholipase C and adenylyl cyclase activities by radioactive methods. The data suggest that for the G(q)-dependent responses, Ca2+, phospholipase C and Elk-1, Nag 26 is a full agonist for both receptors, though of much lower potency. However, saturation was not always reached for OX1, partially due to Nag 26s low solubility and partially because the response decreased at high concentrations. The latter occurs in the same range as some reduction of cell viability, which is independent of orexin receptors. Based on the EC50, Nag 26 was OX2 selective by 20-200 fold in different assays, with some indication of biased agonism (as compared to orexin-A). Nag 26 is a potent orexin receptor agonist with a largely similar pharmacological profile as orexin-A. However, its weaker potency (low-mid micromolar) and low water solubility as well as the non-specific effect in the mid-micromolar range may limit its usefulness under physiological conditions. ; Peer reviewed

وصف الملف: application/pdf

العلاقة: Santeri Suokas, Marja Peltola and Jouni Oksanen (Biochemistry and Cell Biology, Department of Veterinary Biosciences, University of Helsinki) are gratefully acknowledged for technical assistance with the experiments, and Kaj-Roger Hurme (Instrument Centre of Faculty of Agriculture and Forestry, University of Helsinki) and Raija Savolainen (Institute of Biotechnology, University of Helsinki) for all help with the liquid scintillation counting and luminescence measurements, respectively. This work was supported by the European Union (FP7-HEALTHproject GLORIA [# 602919]), the Magnus Ehrnrooth Foundation, the Finnish Cultural Foundation, the Orion Research Foundation, the Liv & Halsa Foundation, and the Doctoral Program in Drug Research of the University of Helsinki.; Rinne , M K , Leino , T O , Turku , A , Turunen , P M , Steynen , Y , Xhaard , H , Wallen , E A A & Kukkonen , J P 2018 , ' Pharmacological characterization of the orexin/hypocretin receptor agonist Nag 26 ' , European Journal of Pharmacology , vol. 837 , pp. 137-144 . https://doi.org/10.1016/j.ejphar.2018.09.003Test; ORCID: /0000-0003-0959-7221/work/49162309; ORCID: /0000-0003-2582-7971/work/49162603; ORCID: /0000-0002-3129-1678/work/49160715; ORCID: /0000-0002-6989-1564/work/63349243; ORCID: /0000-0003-3218-2841/work/68616121; http://hdl.handle.net/10138/305214Test; aff2e1b3-c4b3-4caf-a9e3-98c8277aa516; 85053081769; 000444963400016

الإتاحة: http://hdl.handle.net/10138/305214Test

المؤلفون: Vidilaseris, Keni, Kiriazis, Alexandros, Turku, Ainoleena, Khattab, Ayman, Johansson, Niklas G., Leino, Teppo O., Kiuru, Paula S., Boije af Gennäs, Gustav, Meri, Seppo, Yli-Kauhaluoma, Jari, Xhaard, Henri, Goldman, Adrian

المساهمون: BBSRC, Academy of Finland, The Jane and Aatos Erkko Foundation, University of Helsinki funds

المصدر: Science Advances ; volume 5, issue 5 ; ISSN 2375-2548

الوصف: Novel inhibitors of membrane-bound pyrophosphatases unlock asymmetric conformations by binding near the exit channel.

الإتاحة: https://doi.org/10.1126/sciadv.aav7574Test

المؤلفون: Karhu, Lasse, Weisell, Janne, Turunen, Pauli M., Leino, Teppo O., Pätsi, Henri, Xhaard, Henri, Kukkonen, Jyrki P., Wallén, Erik A.A.

المساهمون: Faculty of Pharmacy, Pharmaceutical Design and Discovery group, Medicum, Veterinary Biosciences, Departments of Faculty of Veterinary Medicine, Faculty of Veterinary Medicine, Division of Pharmaceutical Chemistry and Technology, Henri Xhaard / Principal Investigator, Drug Research Program, Jyrki Kukkonen / Principal Investigator, Veterinary Biochemistry and Cell Biology, Department of Physiology, Erik Wallen / Principal Investigator, Medicinal Chemistry research group

مصطلحات موضوعية: peptide stapling, pseudopeptide, orexin, G protein-coupled receptor, OX1, BINDING, RECOGNITION, APPETITE, LIGANDS, ANALOGS, SYSTEM, ACID, 3111 Biomedicine, 317 Pharmacy, 1182 Biochemistry, cell and molecular biology

الوصف: The peptides orexin-A and -B, the endogenous agonists of the orexin receptors, have similar 19-amino-acid C-termini which retain full maximum response as truncated peptides with only marginally reduced potency, while further N-terminal truncations successively reduce the activity. The peptides have been suggested to bind in an α‐helical conformation, and truncation beyond a certain critical length is likely to disrupt the overall helical structure. In this study, we set out to stabilize the α‐helical conformation of orexin‐A15–33 via peptide stapling at four different sites. At a suggested hinge region, we varied the length of the cross-linker as well as replaced the staple with two α-aminoisobutyric acid residues. Modifications close to the peptide C‐terminus, which is crucial for activity, were not allowed. However, central and N‐terminal modifications yielded bioactive peptides, albeit with decreased potencies. This provides evidence that the orexin receptors can accommodate and be activated by α-helical peptides. The decrease in potency is likely linked to a stabilization of suboptimal peptide conformation or blocking of peptide backbone–receptor interactions at the hinge region by the helical stabilization or the modified amino acids. ; Peer reviewed

وصف الملف: application/pdf

العلاقة: Karhu , L , Weisell , J , Turunen , P M , Leino , T O , Pätsi , H , Xhaard , H , Kukkonen , J P & Wallén , E A A 2018 , ' Stapled truncated orexin peptides as orexin receptor agonists ' , Peptides , vol. 102 , pp. 54-60 . https://doi.org/10.1016/j.peptides.2018.02.004Test; RIS: urn:47A3C83D5A70294343EAE7F9322ED5A3; ORCID: /0000-0003-2582-7971/work/44189377; ORCID: /0000-0001-6432-8580/work/44189445; ORCID: /0000-0002-3129-1678/work/44189234; ORCID: /0000-0002-6989-1564/work/63349261; http://hdl.handle.net/10138/234577Test; 342c7d94-0f56-473a-9ae0-178e813e1e17; 85042934582; 000427917500008

الإتاحة: http://hdl.handle.net/10138/234577Test

المؤلفون: Keurulainen, Leena, Heiskari, Mikko, Nenonen, Satu, Nasereddin, Abedelmajeed, Kopelyanskiy, Dmitry, Leino, Teppo O., Yli-Kauhaluoma, Jari, Jaffe, Charles L., Kiuru, Paula

المساهمون: Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, Jari Yli-Kauhaluoma / Principal Investigator, Drug Discovery, Pharmaceutical Design and Discovery group, Drug Research Program, Medicinal Chemistry research group

مصطلحات موضوعية: IN-VITRO ACTIVITY, INHIBITORS, DESIGN, DRUGS, AMASTIGOTES, DERIVATIVES, CYANATION, ASSAY, 1182 Biochemistry, cell and molecular biology, 317 Pharmacy

الوصف: A facile synthesis route to carboxyimidamide-substituted benzoxadiazoles and related derivatives was developed. A total of 25 derivatives were synthesized. They were evaluated for antileishmanial activity by inhibition of Leishmania donovani axenic amastigote growth using a fluorescent viability microplate assay. The most promising derivative (14) demonstrated an antileishmanial EC50 of 4.0 mu M, and it also showed activity in infected macrophages (EC50 5.92 mu M) without signs of cytotoxicity. ; Peer reviewed

وصف الملف: application/pdf

العلاقة: We thank Ms. Anna Keltikangas nee Takala for the synthesis assistance. This study was supported by the Academy of Finland (projects 264020 and 265481 to JYK). CLJ holds the Michael and Penny Feiwel Professorial Chair of Dermatology.; Keurulainen , L , Heiskari , M , Nenonen , S , Nasereddin , A , Kopelyanskiy , D , Leino , T O , Yli-Kauhaluoma , J , Jaffe , C L & Kiuru , P 2015 , ' Synthesis of carboxyimidamide-substituted benzo[c][1,2,5]oxadiazoles and their analogs, and evaluation of biological activity against Leishmania donovani ' , MedChemComm , vol. 6 , no. 9 , pp. 1673-1678 . https://doi.org/10.1039/c5md00119fTest; ORCID: /0000-0001-8528-7757/work/30218069; ORCID: /0000-0003-0370-7653/work/28760601; ORCID: /0000-0003-2582-7971/work/29942451; ORCID: /0000-0001-6084-684X/work/41128118; http://hdl.handle.net/10138/224652Test; 73e21bf2-65fd-4006-8e14-3f82da4f00a5; 84940939353; 000360639300012

الإتاحة: http://hdl.handle.net/10138/224652Test