1,3-Dialkyl-substituted tetrahydropyrimido[1,2-f]purine-2,4-diones as multiple target drugs for the potential treatment of neurodegenerative diseases

Koch, Pierre; Akkari, Rhalid; Brunschweiger, Andreas; Borrmann, Thomas; Schlenk, Miriam; Küppers, Petra; Köse, Meryem; Radjainia, H.; Hockemeyer, Jörg; Drabczyńska, Anna; Kieć‐Kononowicz, Katarzyna; Müller, Christian

doi:10.1016/j.bmc.2013.09.044

Cited by 27 publications

(16 citation statements)

References 55 publications

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“…Moderate to large species differences have previously been described for different classes of AR antagonists 50. 59, 60 As preclinical in vivo evaluation is typically performed in rodents, mainly rats or mice, we compared affinities of the investigated 1,3‐dimethyltetrahydropyrazino[2,1‐ f ]purinediones at rat and human A 1 and A 2A ARs.…”

Section: Resultsmentioning

confidence: 99%

“…Some of us—in collaboration with the group of K. Kieć‐Kononowocz (Jagiellonian University, Kraków, Poland)—have previously reported the development of tetrahydropyrimido[2,1‐ f ]purinediones 5 (Figure 3), a class of compounds that can be envisaged as tricyclic caffeine derivatives 45–50. They represent structural analogues of 8‐styrylxanthine derivatives, which are sterically constrained by annulation of a tetrahydropyrimidine ring to the 7,8‐position of caffeine mimicking the 8‐ E ‐styryl substructure of A 2A AR antagonists 4 a and 4 b .…”

Section: Introductionmentioning

confidence: 99%

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8‐Benzyltetrahydropyrazino[2,1‐f]purinediones: Water‐Soluble Tricyclic Xanthine Derivatives as Multitarget Drugs for Neurodegenerative Diseases

Brunschweiger¹,

Koch²,

Schlenk³

et al. 2014

ChemMedChem

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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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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

8‐Benzyltetrahydropyrazino[2,1‐f]purinediones: Water‐Soluble Tricyclic Xanthine Derivatives as Multitarget Drugs for Neurodegenerative Diseases

Brunschweiger¹,

Koch²,

Schlenk³

et al. 2014

ChemMedChem

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“…(18) (Mihara et al 2007), JNJ-40255293 (19) (Atack et al 2014), and the tricyclic pyrimidopurinedione 20 (Koch et al 2013).…”

Section: Dual-and Multi-target Approachesmentioning

confidence: 99%

“…Several series of tricyclic pyrimido-and pyrazino-purinediones have been developed with triple inhibition of MAO-B, A 2A -and A 1 ARs ( Brunschweiger et al 2014;Koch et al 2013). The best triple-active compounds were 23-25 (see Table 3.1).…”

Section: Triple a 1 /A 2a Antagonists/mao-b Inhibitorsmentioning

confidence: 99%

Adenosine A2A Receptor Antagonists in Drug Development

Müller

2015

Current Topics in Neurotoxicity

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The first A 2A adenosine receptor antagonist, istradefylline, was approved in 2013 in Japan for the treatment of Parkinson's disease (PD). This will allow long-term studies to elucidate the neuroprotective potential of A 2A antagonists in patients. New A 2A antagonists are in clinical evaluation for PD. Additional promising indications for A 2A antagonists are being explored, including Alzheimer's disease (AD) and other neurodegenerative diseases, depression, and attention deficit hyperactivity disease (ADHD). A 2A antagonists may be useful for the treatment of several rare neurodegenerative diseases, and their clinical evaluation for those diseases is warranted. Dual-and multi-target drugs combining A 2A antagonism with A 1 antagonism, MAO-B inhibition, dopamine receptor activation and/or NMDA receptor blockade may be advantageous for the treatment of PD and perhaps also for other brain diseases. X-ray structure of the human A 2A adenosine receptor in complex with several antagonists and agonists provide a basis for understanding drug-receptor interactions and support the development of new drugs.

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“…We previously reported on the development of tetrahydropyrimido[2,1- f ]purinediones (e.g., compounds 9a , 9b ) as AR antagonists and MAO-B inhibitors (Figure 3 ; Drabczynska et al, 2007 ; Koch et al, 2013 ). This class of compounds can be envisaged as tricyclic caffeine derivatives.…”

Section: Introductionmentioning

confidence: 99%

Probing Substituents in the 1- and 3-Position: Tetrahydropyrazino-Annelated Water-Soluble Xanthine Derivatives as Multi-Target Drugs With Potent Adenosine Receptor Antagonistic Activity

et al. 2018

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Tetrahydropyrazino-annelated theophylline (1,3-dimethylxanthine) derivatives have previously been shown to display increased water-solubility as compared to the parent xanthines due to their basic character. In the present study, we modified this promising scaffold by replacing the 1,3-dimethyl residues by a variety of alkyl groups including combinations of different substituents in both positions. Substituted benzyl or phenethyl residues were attached to the N8 of the resulting 1,3-dialkyl-tetrahydropyrazino[2,1-f ]purinediones with the aim to obtain multi-target drugs that block human A1 and A2A adenosine receptors (ARs) and monoaminoxidase B (MAO-B). 1,3-Diethyl-substituted derivatives showed high affinity for A1 ARs, e.g., 15d (PSB-18339, 8-m-bromobenzyl-substituted) displayed a Ki value of 13.6 nM combined with high selectivity. 1-Ethyl-3-propargyl-substituted derivatives exhibited increased A2A AR affinity. The 8-phenethyl derivative 20h was selective for the A2A AR (Ki 149 nM), while the corresponding 8-benzyl-substituted compound 20e (PSB-1869) blocked A1 and A2A ARs with equal potency (Ki A1, 180 nM; A2A, 282 nM). The 1-ethyl-3-methyl-substituted derivative 16a (PSB-18405) bearing a m,p-dichlorobenzyl residue at N8 blocked all three targets, A1 ARs (Ki 396 nM), A2A ARs (Ki 1,620 nM), and MAO-B (IC50 106 nM) with high selectivity vs. the other subtypes (A2B and A3 ARs, MAO-A), and can thus be considered as a multi-target drug. Our findings were rationalized by molecular docking studies based on previously published X-ray structures of the protein targets. The new drugs have potential for the treatment of neurodegenerative diseases, in particular Parkinson's disease.

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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

Cited by 27 publications

References 55 publications

8‐Benzyltetrahydropyrazino[2,1‐f]purinediones: Water‐Soluble Tricyclic Xanthine Derivatives as Multitarget Drugs for Neurodegenerative Diseases

8‐Benzyltetrahydropyrazino[2,1‐f]purinediones: Water‐Soluble Tricyclic Xanthine Derivatives as Multitarget Drugs for Neurodegenerative Diseases

Adenosine A2A Receptor Antagonists in Drug Development

Probing Substituents in the 1- and 3-Position: Tetrahydropyrazino-Annelated Water-Soluble Xanthine Derivatives as Multi-Target Drugs With Potent Adenosine Receptor Antagonistic Activity

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