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8-Substituted 1,3-dimethyltetrahydropyrazino[2,1-f]purinediones: Water-soluble adenosine receptor antagonists and monoamine oxidase B inhibitors.
Bioorg Med Chem. 2016 11 01; 24(21):5462-5480.BM

Abstract

Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases. Validated targets for the treatment of Parkinson's disease are, among others, the A2A adenosine receptor (AR) and the enzyme monoamine oxidase B (MAO-B). Additional blockade of brain A1 ARs may also be beneficial. We recently described 8-benzyl-substituted tetrahydropyrazino[2,1-f]purinediones as a new lead structure for the development of such multi-target drugs. We have now designed a new series of tetrahydropyrazino[2,1-f]purinediones to extensively explore their structure-activity-relationships. Several compounds blocked human and rat A1 and A2AARs at similar concentrations representing dual A1/A2A antagonists with high selectivity versus the other AR subtypes. Among the best dual A1/A2AAR antagonists were 8-(3-(4-chlorophenyl)propyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (41, Ki human A1: 65.5nM, A2A: 230nM; Ki rat A1: 352nM, A2A: 316nM) and 1,3-dimethyl-8-((2-(thiophen-2-yl)thiazol-4-yl)methyl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (57, Ki human A1: 642nM, A2A: 203nM; Ki rat A1: 166nM, A2A: 121nM). Compound 57 was found to be well water-soluble (0.7mg/mL) at a physiological pH value of 7.4. One of the new compounds showed triple-target inhibition: (R)-1,3-dimethyl-8-(2,1,3,4-tetrahydronaphthalen-1-yl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (49) was about equipotent at A1 and A2AARs and at MAO-B (Ki human A1: 393nM, human A2A: 595nM, IC50 human MAO-B: 210nM) thus allowing future in vivo explorations of the intended multi-target approach.

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Authors+Show Affiliations

Brunschweiger A

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.

CNS Research, Medicinal Chemistry & Lead Generation, UCB S.A., Chemin du Foriest, 1420 Braine l'Alleud, Belgium.

CNS Research, Medicinal Chemistry & Lead Generation, UCB S.A., Chemin du Foriest, 1420 Braine l'Alleud, Belgium.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany. Electronic address: christa.mueller@uni-bonn.de.

MeSH

Adenosine A2 Receptor AntagonistsAnimalsCHO CellsCricetulusDose-Response Relationship, DrugHumansMolecular StructureMonoamine OxidaseMonoamine Oxidase InhibitorsPurinesPyrazinesRatsReceptor, Adenosine A2ASolubilityStructure-Activity RelationshipWater

Pub Type(s)

Journal Article

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

Language

eng

PubMed ID

27658798

Citation

Brunschweiger, Andreas, et al. "8-Substituted 1,3-dimethyltetrahydropyrazino[2,1-f]purinediones: Water-soluble Adenosine Receptor Antagonists and Monoamine Oxidase B Inhibitors." Bioorganic & Medicinal Chemistry, vol. 24, no. 21, 2016, pp. 5462-5480.

Brunschweiger A, Koch P, Schlenk M, et al. 8-Substituted 1,3-dimethyltetrahydropyrazino[2,1-f]purinediones: Water-soluble adenosine receptor antagonists and monoamine oxidase B inhibitors. Bioorg Med Chem. 2016;24(21):5462-5480.

Brunschweiger, A., Koch, P., Schlenk, M., Rafehi, M., Radjainia, H., Küppers, P., Hinz, S., Pineda, F., Wiese, M., Hockemeyer, J., Heer, J., Denonne, F., & Müller, C. E. (2016). 8-Substituted 1,3-dimethyltetrahydropyrazino[2,1-f]purinediones: Water-soluble adenosine receptor antagonists and monoamine oxidase B inhibitors. Bioorganic & Medicinal Chemistry, 24(21), 5462-5480. https://doi.org/10.1016/j.bmc.2016.09.003

Brunschweiger A, et al. 8-Substituted 1,3-dimethyltetrahydropyrazino[2,1-f]purinediones: Water-soluble Adenosine Receptor Antagonists and Monoamine Oxidase B Inhibitors. Bioorg Med Chem. 2016 11 1;24(21):5462-5480. PubMed PMID: 27658798.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - 8-Substituted 1,3-dimethyltetrahydropyrazino[2,1-f]purinediones: Water-soluble adenosine receptor antagonists and monoamine oxidase B inhibitors. AU - Brunschweiger,Andreas, AU - Koch,Pierre, AU - Schlenk,Miriam, AU - Rafehi,Muhammad, AU - Radjainia,Hamid, AU - Küppers,Petra, AU - Hinz,Sonja, AU - Pineda,Felipe, AU - Wiese,Michael, AU - Hockemeyer,Jörg, AU - Heer,Jag, AU - Denonne,Frédéric, AU - Müller,Christa E, Y1 - 2016/09/03/ PY - 2016/05/19/received PY - 2016/08/15/revised PY - 2016/09/01/accepted PY - 2016/9/24/pubmed PY - 2017/8/5/medline PY - 2016/9/24/entrez KW - Alzheimer’s disease KW - Anellated xanthines KW - Caffeine derivatives KW - Heterocycles KW - Neurodegenerative disease KW - Parkinson’s disease: synthesis KW - Polypharmacology KW - Water-solubility KW - Xanthines SP - 5462 EP - 5480 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 24 IS - 21 N2 - Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases. Validated targets for the treatment of Parkinson's disease are, among others, the A2A adenosine receptor (AR) and the enzyme monoamine oxidase B (MAO-B). Additional blockade of brain A1 ARs may also be beneficial. We recently described 8-benzyl-substituted tetrahydropyrazino[2,1-f]purinediones as a new lead structure for the development of such multi-target drugs. We have now designed a new series of tetrahydropyrazino[2,1-f]purinediones to extensively explore their structure-activity-relationships. Several compounds blocked human and rat A1 and A2AARs at similar concentrations representing dual A1/A2A antagonists with high selectivity versus the other AR subtypes. Among the best dual A1/A2AAR antagonists were 8-(3-(4-chlorophenyl)propyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (41, Ki human A1: 65.5nM, A2A: 230nM; Ki rat A1: 352nM, A2A: 316nM) and 1,3-dimethyl-8-((2-(thiophen-2-yl)thiazol-4-yl)methyl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (57, Ki human A1: 642nM, A2A: 203nM; Ki rat A1: 166nM, A2A: 121nM). Compound 57 was found to be well water-soluble (0.7mg/mL) at a physiological pH value of 7.4. One of the new compounds showed triple-target inhibition: (R)-1,3-dimethyl-8-(2,1,3,4-tetrahydronaphthalen-1-yl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (49) was about equipotent at A1 and A2AARs and at MAO-B (Ki human A1: 393nM, human A2A: 595nM, IC50 human MAO-B: 210nM) thus allowing future in vivo explorations of the intended multi-target approach. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/27658798/8_Substituted_13_dimethyltetrahydropyrazino[21_f]purinediones:_Water_soluble_adenosine_receptor_antagonists_and_monoamine_oxidase_B_inhibitors_ DB - PRIME DP - Unbound Medicine ER -