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1,3-Dialkyl-substituted tetrahydropyrimido[1,2-f]purine-2,4-diones as multiple target drugs for the potential treatment of neurodegenerative diseases.
Bioorg Med Chem. 2013 Dec 01; 21(23):7435-52.BM

Abstract

Adenosine receptors and monoamine oxidases are drug targets for neurodegenerative diseases such as Parkinson's and Alzheimer's disease. In the present study we prepared a library of 55 mostly novel tetrahydropyrimido[2,1-f]purinediones with various substituents in the 1- and 3-position (1,3-dimethyl, 1,3-diethyl, 1,3-dipropyl, 1-methyl-3-propargyl) and broad variation in the 9-position. A synthetic strategy to obtain 3-propargyl-substituted tetrahydropyrimido[2,1-f]purinedione derivatives was developed. The new compounds were evaluated for their interaction with all four adenosine receptor subtypes and for their ability to inhibit monoamine oxidases (MAO). Introduction of mono- or di-chloro-substituted phenyl, benzyl or phenethyl residues at N9 of the 1,3-dimethyl series led to the discovery of a novel class of potent MAO-B inhibitors, the most potent compound being 9-(3,4-dichlorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)-dione (21g, IC(50) human MAO-B: 0.0629 μM), which displayed high selectivity versus the other investigated targets. Potent dually active A1/A2A adenosine receptor antagonists were identified, for example, 9-benzyl-1-methyl-3-propargyl-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)dione (19f, Ki, human receptors, A1: 0.249 μM, A2A: 0.253 μM). Several compounds showed triple-target inhibition, the best compound being 9-(2-methoxybenzyl)-1-methyl-3-(prop-2-ynyl)-6,7,8,9-tetrahydro pyrimido [1,2-f]purine-2,4(1H,3H)-dione (19g, Ki A1: 0.605 μM, Ki A2A: 0.417 μM, IC(50) MAO-B: 1.80 μM). Compounds inhibiting several different targets involved in neurodegeneration may exhibit additive or even synergistic effects in vivo.

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Authors+Show Affiliations

Koch P
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Akkari R
No affiliation info available
Brunschweiger A
No affiliation info available
Borrmann T
No affiliation info available
Schlenk M
No affiliation info available
Küppers P
No affiliation info available
Köse M
No affiliation info available
Radjainia H
No affiliation info available
Hockemeyer J
No affiliation info available
Drabczyńska A
No affiliation info available
Kieć-Kononowicz K
No affiliation info available
Müller CE
No affiliation info available

MeSH

Adenosine A1 Receptor AntagonistsAdenosine A2 Receptor AntagonistsAnimalsCHO CellsCaffeineCricetulusHumansMonoamine OxidaseMonoamine Oxidase InhibitorsNeurodegenerative DiseasesPurinergic P1 Receptor AntagonistsPurinesXanthines

Pub Type(s)

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

Language

eng

PubMed ID

24139167

Citation

Koch, Pierre, et al. "1,3-Dialkyl-substituted Tetrahydropyrimido[1,2-f]purine-2,4-diones as Multiple Target Drugs for the Potential Treatment of Neurodegenerative Diseases." Bioorganic & Medicinal Chemistry, vol. 21, no. 23, 2013, pp. 7435-52.
Koch P, Akkari R, Brunschweiger A, et al. 1,3-Dialkyl-substituted tetrahydropyrimido[1,2-f]purine-2,4-diones as multiple target drugs for the potential treatment of neurodegenerative diseases. Bioorg Med Chem. 2013;21(23):7435-52.
Koch, P., Akkari, R., Brunschweiger, A., Borrmann, T., Schlenk, M., Küppers, P., Köse, M., Radjainia, H., Hockemeyer, J., Drabczyńska, A., Kieć-Kononowicz, K., & Müller, C. E. (2013). 1,3-Dialkyl-substituted tetrahydropyrimido[1,2-f]purine-2,4-diones as multiple target drugs for the potential treatment of neurodegenerative diseases. Bioorganic & Medicinal Chemistry, 21(23), 7435-52. https://doi.org/10.1016/j.bmc.2013.09.044
Koch P, et al. 1,3-Dialkyl-substituted Tetrahydropyrimido[1,2-f]purine-2,4-diones as Multiple Target Drugs for the Potential Treatment of Neurodegenerative Diseases. Bioorg Med Chem. 2013 Dec 1;21(23):7435-52. PubMed PMID: 24139167.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 1,3-Dialkyl-substituted tetrahydropyrimido[1,2-f]purine-2,4-diones as multiple target drugs for the potential treatment of neurodegenerative diseases. AU - Koch,Pierre, AU - Akkari,Rhalid, AU - Brunschweiger,Andreas, AU - Borrmann,Thomas, AU - Schlenk,Miriam, AU - Küppers,Petra, AU - Köse,Meryem, AU - Radjainia,Hamid, AU - Hockemeyer,Jörg, AU - Drabczyńska,Anna, AU - Kieć-Kononowicz,Katarzyna, AU - Müller,Christa E, Y1 - 2013/09/25/ PY - 2013/08/09/received PY - 2013/09/14/revised PY - 2013/09/17/accepted PY - 2013/10/22/entrez PY - 2013/10/22/pubmed PY - 2014/5/20/medline KW - Adenosine A(1) receptor antagonists KW - Adenosine A(2A) receptor antagonists KW - Alzheimer’s disease KW - Anellated xanthines KW - Caffeine derivatives KW - Monoamine oxidase B inhibitors KW - Parkinson’s disease KW - Synthesis KW - Tetrahydropyrimido[2,1-f]purinediones KW - Tricyclic compounds SP - 7435 EP - 52 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 21 IS - 23 N2 - Adenosine receptors and monoamine oxidases are drug targets for neurodegenerative diseases such as Parkinson's and Alzheimer's disease. In the present study we prepared a library of 55 mostly novel tetrahydropyrimido[2,1-f]purinediones with various substituents in the 1- and 3-position (1,3-dimethyl, 1,3-diethyl, 1,3-dipropyl, 1-methyl-3-propargyl) and broad variation in the 9-position. A synthetic strategy to obtain 3-propargyl-substituted tetrahydropyrimido[2,1-f]purinedione derivatives was developed. The new compounds were evaluated for their interaction with all four adenosine receptor subtypes and for their ability to inhibit monoamine oxidases (MAO). Introduction of mono- or di-chloro-substituted phenyl, benzyl or phenethyl residues at N9 of the 1,3-dimethyl series led to the discovery of a novel class of potent MAO-B inhibitors, the most potent compound being 9-(3,4-dichlorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)-dione (21g, IC(50) human MAO-B: 0.0629 μM), which displayed high selectivity versus the other investigated targets. Potent dually active A1/A2A adenosine receptor antagonists were identified, for example, 9-benzyl-1-methyl-3-propargyl-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)dione (19f, Ki, human receptors, A1: 0.249 μM, A2A: 0.253 μM). Several compounds showed triple-target inhibition, the best compound being 9-(2-methoxybenzyl)-1-methyl-3-(prop-2-ynyl)-6,7,8,9-tetrahydro pyrimido [1,2-f]purine-2,4(1H,3H)-dione (19g, Ki A1: 0.605 μM, Ki A2A: 0.417 μM, IC(50) MAO-B: 1.80 μM). Compounds inhibiting several different targets involved in neurodegeneration may exhibit additive or even synergistic effects in vivo. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/24139167/13_Dialkyl_substituted_tetrahydropyrimido[12_f]purine_24_diones_as_multiple_target_drugs_for_the_potential_treatment_of_neurodegenerative_diseases_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(13)00824-9 DB - PRIME DP - Unbound Medicine ER -