0000000000330680

AUTHOR

Markku Pasanen

showing 3 related works from this author

Structure-Activity Relationship Analysis of 3-Phenylcoumarin-Based Monoamine Oxidase B Inhibitors

2018

Monoamine oxidase B (MAO-B) catalyzes deamination of monoamines such as neurotransmitters dopamine and norepinephrine. Accordingly, small-molecule MAO-B inhibitors potentially alleviate the symptoms of dopamine-linked neuropathologies such as depression or Parkinson's disease. Coumarin with a functionalized 3-phenyl ring system is a promising scaffold for building potent MAO-B inhibitors. Here, a vast set of 3-phenylcoumarin derivatives was designed using virtual combinatorial chemistry or rationally de novo and synthesized using microwave chemistry. The derivatives inhibited the MAO-B at 100 nM−1 μM. The IC50 value of the most potent derivative 1 was 56 nM. A docking-based structure-activi…

0301 basic medicineentsyymitParkinson's diseaseParkinsonin tautita311101 natural scienceslääkesuunnittelumonoamine oxidase B (MAO-B)lcsh:Chemistry03 medical and health scienceschemistry.chemical_compoundstructure-activity relationship (SAR)Dopamine3-phenylcoumarinmedicineStructure–activity relationshipoksidoreduktaasitkumariinitta116ta317inhibiittoritOriginal Researchchemistry.chemical_classificationbiologyvirtual drug designta1182General ChemistryCoumarin3. Good health0104 chemical sciences010404 medicinal & biomolecular chemistryChemistry030104 developmental biologyMonoamine neurotransmitterEnzymeBiochemistrychemistrylcsh:QD1-999Docking (molecular)biology.proteinParkinson’s diseaseMonoamine oxidase BMonoamine oxidase Amedicine.drugFrontiers in Chemistry
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Blocking oestradiol synthesis pathways with potent and selective coumarin derivatives

2018

A comprehensive set of 3-phenylcoumarin analogues with polar substituents was synthesised for blocking oestradiol synthesis by 17-b-hydroxysteroid dehydrogenase 1 (HSD1) in the latter part of the sulphatase pathway. Five analogues produced 62% HSD1 inhibition at 5 mM and, furthermore, three of them produced 68% inhibition at 1 mM. A docking-based structure-activity relationship analysis was done to determine the molecular basis of the inhibition and the cross-reactivity of the analogues was tested against oestrogen receptor, aromatase, cytochrome P450 1A2, and monoamine oxidases. Most of the analogues are only modestly active with 17-b-hydroxysteroid dehydrogenase 2 – a requirement for lowe…

0301 basic medicinearomatase17-Hydroxysteroid Dehydrogenasesmedicine.drug_classStereochemistry3-imidazolecoumarinaromataasiDehydrogenaseta3111LigandsStructure-Activity Relationship03 medical and health scienceschemistry.chemical_compoundstructure-activity relationship (SAR)0302 clinical medicineCoumarinsIn vivo17-β-hydroxysteroid dehydrogenase 1 (HSD1)Drug DiscoverymedicineHumansMoietyEnzyme InhibitorsAromatasePharmacologyAromatase inhibitorDose-Response Relationship DrugEstradiolMolecular StructurebiologyChemistrylcsh:RM1-950CYP1A2ta1182General MedicineCoumarin3. Good healthMolecular Docking Simulationlcsh:Therapeutics. Pharmacology030104 developmental biologyDocking (molecular)030220 oncology & carcinogenesisbiology.proteinComputer-Aided Design3-Phenylcoumarinhormones hormone substitutes and hormone antagonistsResearch PaperJournal of Enzyme Inhibition and Medicinal Chemistry
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Inhibitory effects and oxidation of 6-methylcoumarin, 7-methylcoumarin and 7-formylcoumarin via human CYP2A6 and its mouse and pig orthologous enzymes

2015

1. Information about the metabolism of compounds is essential in drug discovery and development, risk assessment of chemicals and further development of predictive methods. 2. In vitro and in silico methods were applied to evaluate the metabolic and inhibitory properties of 6-methylcoumarin, 7-methylcoumarin and 7-formylcoumarin with human CYP2A6, mouse CYP2A5 and pig CYP2A19. 3. 6-Methylcoumarin was oxidized to fluorescent 7-hydroxy-6-methylcoumarin by CYP2A6 (Km: 0.64-0.91 µM; Vmax: 0.81-0.89 min(-1)) and by CYP2A5 and CYP2A19. The reaction was almost completely inhibited at 10 µM 7-methylcoumarin in liver microsomes of human and mouse, but in pig only 40% inhibition was obtained with the…

Models Molecular0301 basic medicineenzyme assayTime Factorscoumarin derivativecytochrome P450Health Toxicology and MutagenesisIn silicoSus scrofaHydroxylationToxicologyta3111BiochemistryCytochrome P-450 CYP2A6Inhibitory Concentration 50Mice03 medical and health sciencesCoumarinsmedicineAnimalsCytochrome P-450 Enzyme InhibitorsHumansCYP2A6ta317Pharmacologychemistry.chemical_classificationbiologyMethoxsalenta1182Cytochrome P450General MedicineMetabolismMolecular biologyIn vitroEnzyme assayKinetics030104 developmental biologyEnzymeBiochemistrychemistrybiology.proteinfluorescenceOxidation-Reductionmetabolismmedicine.drugXenobiotica
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