title: 1,3-Dialkyl-substituted tetrahydropyrimido[1,2-f]purine-2,4-diones as multiple target drugs for the potential treatment of neurodegenerative diseases.
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.
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Pierre
authors.initials: P
authors.lastname: Koch
authors.forename: Rhalid
authors.initials: R
authors.lastname: Akkari
authors.forename: Andreas
authors.initials: A
authors.lastname: Brunschweiger
authors.forename: Thomas
authors.initials: T
authors.lastname: Borrmann
authors.forename: Miriam
authors.initials: M
authors.lastname: Schlenk
authors.forename: Petra
authors.initials: P
authors.lastname: Küppers
authors.forename: Meryem
authors.initials: M
authors.lastname: Köse
authors.forename: Hamid
authors.initials: H
authors.lastname: Radjainia
authors.forename: Jörg
authors.initials: J
authors.lastname: Hockemeyer
authors.forename: Anna
authors.initials: A
authors.lastname: Drabczyńska
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002110:Caffeine / Q000737:chemistry / Q000494:pharmacology; D003412:Cricetulus; D006801:Humans; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000201:enzymology; D058915:Purinergic P1 Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology*; D014970:Xanthines / Q000737:chemistry / Q000494:pharmacology
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D008996:Monoamine Oxidase Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines; D014970:Xanthines; D002110:Caffeine; D008995:Monoamine Oxidase; C030985:purine
keywords: Adenosine A(1) receptor antagonists; Adenosine A(2A) receptor antagonists; Alzheimer’s disease; Anellated xanthines; Caffeine derivatives; Monoamine oxidase B inhibitors; Parkinson’s disease; Synthesis; Tetrahydropyrimido[2,1-f]purinediones; Tricyclic compounds