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8-Benzyltetrahydropyrazino[2,1-f]purinediones: water-soluble tricyclic xanthine derivatives as multitarget drugs for neurodegenerative diseases.
ChemMedChem. 2014 Aug; 9(8):1704-24.C

Abstract

8-Benzyl-substituted tetrahydropyrazino[2,1-f]purinediones were designed as tricyclic xanthine derivatives containing a basic nitrogen atom in the tetrahydropyrazine ring to improve water solubility. A library of 69 derivatives was prepared and evaluated in radioligand binding studies at adenosine receptor (AR) subtypes and for their ability to inhibit monoamine oxidases (MAO). Potent dual-target-directed A1 /A2A adenosine receptor antagonists were identified. Several compounds showed triple-target inhibition; one of the best compounds was 8-(2,4-dichloro-5-fluorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (72) (human AR: Ki A1 217 nM, A2A 233 nM; IC50 MAO-B: 508 nM). Dichlorinated compound 36 [8-(3,4-dichlorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione] was found to be the best triple-target drug in rat (Ki A1 351 nM, A2A 322 nm; IC50 MAO-B: 260 nM), and may serve as a useful tool for preclinical proof-of-principle studies. Compounds that act at multiple targets relevant for symptomatic as well as disease-modifying treatment of neurodegenerative diseases are expected to show advantages over single-target therapeutics.

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Authors+Show Affiliations

Brunschweiger A
Pharmaceutical Chemistry I, Pharmaceutical Institute, PharmaCenter Bonn, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany); Faculty for Chemistry and Chemical Biology TU Dortmund, Otto-Hahn-Straβe 6, 44227 Dortmund (Germany).
Koch P
No affiliation info available
Schlenk M
No affiliation info available
Pineda F
No affiliation info available
Küppers P
No affiliation info available
Hinz S
No affiliation info available
Köse M
No affiliation info available
Ullrich S
No affiliation info available
Hockemeyer J
No affiliation info available
Wiese M
No affiliation info available
Heer J
No affiliation info available
Müller CE
No affiliation info available

MeSH

AnimalsHalf-LifeHumansMicrosomes, LiverMonoamine OxidaseMonoamine Oxidase InhibitorsNeurodegenerative DiseasesRatsSolubilityStructure-Activity RelationshipWaterXanthines

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24817533

Citation

Brunschweiger, Andreas, et al. "8-Benzyltetrahydropyrazino[2,1-f]purinediones: Water-soluble Tricyclic Xanthine Derivatives as Multitarget Drugs for Neurodegenerative Diseases." ChemMedChem, vol. 9, no. 8, 2014, pp. 1704-24.
Brunschweiger A, Koch P, Schlenk M, et al. 8-Benzyltetrahydropyrazino[2,1-f]purinediones: water-soluble tricyclic xanthine derivatives as multitarget drugs for neurodegenerative diseases. ChemMedChem. 2014;9(8):1704-24.
Brunschweiger, A., Koch, P., Schlenk, M., Pineda, F., Küppers, P., Hinz, S., Köse, M., Ullrich, S., Hockemeyer, J., Wiese, M., Heer, J., & Müller, C. E. (2014). 8-Benzyltetrahydropyrazino[2,1-f]purinediones: water-soluble tricyclic xanthine derivatives as multitarget drugs for neurodegenerative diseases. ChemMedChem, 9(8), 1704-24. https://doi.org/10.1002/cmdc.201402082
Brunschweiger A, et al. 8-Benzyltetrahydropyrazino[2,1-f]purinediones: Water-soluble Tricyclic Xanthine Derivatives as Multitarget Drugs for Neurodegenerative Diseases. ChemMedChem. 2014;9(8):1704-24. PubMed PMID: 24817533.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 8-Benzyltetrahydropyrazino[2,1-f]purinediones: water-soluble tricyclic xanthine derivatives as multitarget drugs for neurodegenerative diseases. AU - Brunschweiger,Andreas, AU - Koch,Pierre, AU - Schlenk,Miriam, AU - Pineda,Felipe, AU - Küppers,Petra, AU - Hinz,Sonja, AU - Köse,Meryem, AU - Ullrich,Stefan, AU - Hockemeyer,Jörg, AU - Wiese,Michael, AU - Heer,Jag, AU - Müller,Christa E, Y1 - 2014/05/09/ PY - 2014/03/23/received PY - 2014/5/13/entrez PY - 2014/5/13/pubmed PY - 2015/3/31/medline KW - adenosine receptors KW - antagonists KW - inhibitors KW - monoamine oxidases KW - multitarget drugs KW - neurodegenerative diseases SP - 1704 EP - 24 JF - ChemMedChem JO - ChemMedChem VL - 9 IS - 8 N2 - 8-Benzyl-substituted tetrahydropyrazino[2,1-f]purinediones were designed as tricyclic xanthine derivatives containing a basic nitrogen atom in the tetrahydropyrazine ring to improve water solubility. A library of 69 derivatives was prepared and evaluated in radioligand binding studies at adenosine receptor (AR) subtypes and for their ability to inhibit monoamine oxidases (MAO). Potent dual-target-directed A1 /A2A adenosine receptor antagonists were identified. Several compounds showed triple-target inhibition; one of the best compounds was 8-(2,4-dichloro-5-fluorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (72) (human AR: Ki A1 217 nM, A2A 233 nM; IC50 MAO-B: 508 nM). Dichlorinated compound 36 [8-(3,4-dichlorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione] was found to be the best triple-target drug in rat (Ki A1 351 nM, A2A 322 nm; IC50 MAO-B: 260 nM), and may serve as a useful tool for preclinical proof-of-principle studies. Compounds that act at multiple targets relevant for symptomatic as well as disease-modifying treatment of neurodegenerative diseases are expected to show advantages over single-target therapeutics. SN - 1860-7187 UR - https://www.unboundmedicine.com/medline/citation/24817533/8_Benzyltetrahydropyrazino[21_f]purinediones:_water_soluble_tricyclic_xanthine_derivatives_as_multitarget_drugs_for_neurodegenerative_diseases_ DB - PRIME DP - Unbound Medicine ER -