Publications by authors named "Flavia Varano"

60 Publications

Special Issue "Adenosine Receptors as Attractive Targets in Human Diseases".

Pharmaceuticals (Basel) 2021 Feb 10;14(2). Epub 2021 Feb 10.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Universita' degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy.

The idea of promoting this Special Issue arises from the desire to witness the multidisciplinary efforts that are currently in progress to provide new insights into the pathophysiological role of adenosine [...].
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http://dx.doi.org/10.3390/ph14020140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916353PMC
February 2021

Piperazine- and Piperidine-Containing Thiazolo[5,4-]pyrimidine Derivatives as New Potent and Selective Adenosine A Receptor Inverse Agonists.

Pharmaceuticals (Basel) 2020 Jul 24;13(8). Epub 2020 Jul 24.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Universita'degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy.

The therapeutic use of A adenosine receptor (AR) antagonists for the treatment of neurodegenerative disorders, such as Parkinson and Alzheimer diseases, is a very promising approach. Moreover, the potential therapeutic role of A AR antagonists to avoid both immunoescaping of tumor cells and tumor development is well documented. Herein, we report on the synthesis and biological evaluation of a new set of piperazine- and piperidine- containing 7-amino-2-(furan-2-yl)thiazolo[5,4-]pyrimidine derivatives designed as human A AR antagonists/inverse agonists. Binding and potency data indicated that a good number of potent and selective hA AR inverse agonists were found. Amongst them, the 2-(furan-2-yl)--(2-(4-phenylpiperazin-1-yl)ethyl)thiazolo[5,4-]pyrimidine-5,7-diamine exhibited the highest A AR binding affinity (K = 8.62 nM) as well as inverse agonist potency (IC = 7.42 nM). In addition, bioinformatics prediction using the web tool SwissADME revealed that , , and possessed good drug-likeness profiles.
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http://dx.doi.org/10.3390/ph13080161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465344PMC
July 2020

Discovery of first-in-class multi-target adenosine A receptor antagonists-carbonic anhydrase IX and XII inhibitors. 8-Amino-6-aryl-2-phenyl-1,2,4-triazolo [4,3-a]pyrazin-3-one derivatives as new potential antitumor agents.

Eur J Med Chem 2020 Sep 12;201:112478. Epub 2020 Jun 12.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy. Electronic address:

This paper describes identification of the first-in-class multi-target adenosine A receptor antagonists-carbonic anhydrase (CA) IX and XII inhibitors, as new potential antitumor agents. To obtain the multi-acting ligands, the 8-amino-2,6-diphenyltriazolo[4,3-a]pyrazin-3-one, a potent adenosine hA receptor (AR) antagonist, was taken as lead compound. To address activity against the tumor-associated CA isoforms, it was modified by introduction of different substituents (OH, COOH, CONHOH, SONH) on the 6-phenyl ring or on a phenyl pendant connected to the former through different spacers. Among the new triazolopyrazines 1-23, the most active were those featuring the sulfonamide residue. Derivative 20, featuring a 4-sulfonamidophenyl residue attached through a CONH(CH)CONH spacer at the para-position of the 6-phenyl ring, showed the best combination of activity at the three targets. In fact, it inhibited both the tumor-associated hCA IX and XII isozymes at nanomolar concentration (K = 5.0 and 27.0 nM), and also displayed a quite good affinity for the hA AR (K = 108 nM). Compound 14, bearing the 4-sulfonamidophenyl residue linked at the para-position of the 6-phenyl ring by a CONH spacer, was remarkable because both its hA AR affinity and hCA XII inhibitory potency were in the low nanomolar range (K = 6.4 and 6.2 nM, respectively). Molecular docking studies highlighted the interaction mode of selected triazolopyrazines in the hA AR recognition pocket and in the active site of hCA II, IX and XII isoforms.
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http://dx.doi.org/10.1016/j.ejmech.2020.112478DOI Listing
September 2020

Adenosine A receptors inhibit K currents and cell differentiation in cultured oligodendrocyte precursor cells and modulate sphingosine-1-phosphate signaling pathway.

Biochem Pharmacol 2020 07 3;177:113956. Epub 2020 Apr 3.

Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Italy.

Oligodendrocytes are the only myelinating cells in the brain and differentiate from their progenitors (OPCs) throughout adult life. However, this process fails in demyelinating pathologies. Adenosine is emerging as an important player in OPC differentiation and we recently demonstrated that adenosine A receptors inhibit cell maturation by reducing voltage-dependent K currents. No data are available to date about the A receptor (AR) subtype. The bioactive lipid mediator sphingosine-1-phosphate (S1P) and its receptors (S1P) are also crucial modulators of OPC development. An interaction between this pathway and the AR is reported in peripheral cells. We studied the role of ARs in modulating K currents and cell differentiation in OPC cultures and we investigated a possible interplay with S1P signaling. Our data indicate that the AR agonist BAY60-6583 and its new analogue P453 inhibit K currents in cultured OPC and the effect was prevented by the AR antagonist MRS1706, by K channel blockers and was differently modulated by the S1P analogue FTY720-P. An acute (10 min) exposure of OPCs to BAY60-6583 also increased the phosphorylated form of sphingosine kinase 1 (SphK1). A chronic (7 days) treatment with the same agonist decreased OPC differentiation whereas SphK1/2 inhibition exerted the opposite effect. Furthermore, AR was overexpressed during OPC differentiation, an effect prevented by the pan SphK1/2 inhibitor VPC69047. Finally, AR silenced cells showed increased cell maturation, decreased SphK1 expression and enhanced S1P lyase levels. We conclude that ARs inhibit K currents and cell differentiation and positively modulate S1P synthesis in cultured OPCs.
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http://dx.doi.org/10.1016/j.bcp.2020.113956DOI Listing
July 2020

New 8-amino-1,2,4-triazolo[4,3-a]pyrazin-3-one derivatives. Evaluation of different moieties on the 6-aryl ring to obtain potent and selective human A adenosine receptor antagonists.

Bioorg Med Chem Lett 2020 06 24;30(11):127126. Epub 2020 Mar 24.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy. Electronic address:

In this work, further structural investigations on the 8-amino-2-phenyl-6-aryl-1,2,4-triazolo[4,3-a]pyrazin-3-one series were carried out to achieve potent and selective human A adenosine receptor (AR) antagonists. Different ether and amide moieties were attached at the para-position of the 6-phenyl ring, thus leading to compounds 1-9 and 10-18, respectively. Most of these moieties contained terminal basic rings (pyrrolidine, morpholine, piperidine and substituted piperazines) which were thought to confer good physicochemical and drug-like properties. Compounds 11-16, bearing the amide linker, possessed high affinity and selectivity for the hA AR (K = 3.6-11.8 nM). Also derivatives 1-9, featuring an ether linker, preferentially targeted the hA AR but with lower affinity, compared to those of the relative amide compounds. Docking studies, carried out at the hA AR binding site, highlighted some crucial ligand-receptor interactions, particularly those provided by the appended substituent whose nature deeply affected hA AR affinity.
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http://dx.doi.org/10.1016/j.bmcl.2020.127126DOI Listing
June 2020

Structural investigation on thiazolo[5,4-d]pyrimidines to obtain dual-acting blockers of CD73 and adenosine A receptor as potential antitumor agents.

Bioorg Med Chem Lett 2020 05 29;30(9):127067. Epub 2020 Feb 29.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy.

Adenosine pathway, including its generating enzyme (CD73) and its receptors represents a key target for cancer immunotherapy. Here we aimed to search for novel compounds able to co-target the CD73 and the A adenosine receptor (A AR) as dual-blockers of adenosine generation and activity. The design project was to combine in the same molecule the thiazolo[5,4-d]pyrimidine core, an essential pharmacophoric feature to block the A AR, with a benzenesulfonamide group which is a characteristic group of CD73 inhibitors. Most of the reported compounds resulted in inverse agonists of the human (h) A AR endowed with high affinity, selectivity and potency. However they were weak inhibitors of CD73 enzyme. Nevertheless, this study can be considered as a starting point to develop more active compounds.
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http://dx.doi.org/10.1016/j.bmcl.2020.127067DOI Listing
May 2020

Amino-3,5-Dicyanopyridines Targeting the Adenosine Receptors Ranging from Pan Ligands to Combined A/A Partial Agonists.

Pharmaceuticals (Basel) 2019 Oct 22;12(4). Epub 2019 Oct 22.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy.

The amino-3,5-dicyanopyridine derivatives belong to an intriguing series of adenosine receptor (AR) ligands that has been developed by both academic researchers and industry. Indeed, the studies carried out to date underline the versatility of the dicyanopyridine scaffold to obtain AR ligands with not only a wide range of affinities but also with diverse degrees of efficacies at the different ARs. These observations prompted us to investigate on the structure-activity relationships (SARs) of this series leading to important previously reported results. The present SAR study has helped to confirm the 1-imidazol-2-yl group at R position as an important feature for producing potent AR agonists. Moreover, the nature of the R substituent highly affects not only affinity/activity at the hA and hA ARs but also selectivity versus the other subtypes. Potent hA and hA AR ligands were developed, and among them, the 2-amino-6-[(1-imidazol-2-ylmethyl)sulfanyl]-4-[4-(prop-2-en-1-yloxy)phenyl]pyridine-3,5-dicarbonitrile () is active in the low nanomolar range at these subtypes and shows a good trend of selectivity versus both the hA and hA ARs. This combined hAhA partial agonist activity leads to a synergistic effect on glucose homeostasis and could potentially be beneficial in treating diabetes and related complications.
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http://dx.doi.org/10.3390/ph12040159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958422PMC
October 2019

Antioxidant-Conjugated 1,2,4-Triazolo[4,3-]pyrazin-3-one Derivatives: Highly Potent and Selective Human A Adenosine Receptor Antagonists Possessing Protective Efficacy in Neuropathic Pain.

J Med Chem 2019 09 10;62(18):8511-8531. Epub 2019 Sep 10.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università degli Studi di Firenze , Via Ugo Schiff, 6 , 50019 Sesto Fiorentino , Italy.

New 8-amino-6-aryl-1,2,4-triazolo[4,3-]pyrazin-3-ones were designed to obtain dual antioxidant-human A adenosine receptor (hA AR) antagonists. Two sets of compounds were synthesized, the first featuring phenol rings at the 6-position, the second bearing the lipoyl and 4-hydroxy-3,5-di-but-benzoyl residues appended by different linkers on the 6-phenyl ring. Several new triazolopyrazines () were potent and selective hA AR antagonists ( = 0.17-54.5 nM). Compounds , , and , featuring antioxidant moieties, and compound , lacking the antioxidant functionality, reduced oxaliplatin-induced toxicity in microglia cells, the most active being the lipoyl-derivative and the (4-hydroxy-3,5-di--butyl)benzoyl-analogue which were effective in reducing the oxygen free radical level. The lipoyl-derivative was also able to revert oxaliplatin-induced neuropathy in the mouse. In vivo efficacy of makes it a promising neuroprotective agent in oxidative stress-related diseases.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00778DOI Listing
September 2019

Modifications on the Amino-3,5-dicyanopyridine Core To Obtain Multifaceted Adenosine Receptor Ligands with Antineuropathic Activity.

J Med Chem 2019 08 26;62(15):6894-6912. Epub 2019 Jul 26.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università degli Studi di Firenze , Via Ugo Schiff, 6 , 50019 Sesto Fiorentino , Italy.

A new series of amino-3,5-dicyanopyridines () was synthesized and biologically evaluated in order to further investigate the potential of this scaffold to obtain adenosine receptor (AR) ligands. In general, the modifications performed have led to compounds having high to good human (h) AAR affinity and an inverse agonist profile. While most of the compounds are hAAR-selective, some derivatives behave as mixed hAAR inverse agonists/A and A AR antagonists. The latter compounds ( showed that they reduce oxaliplatin-induced neuropathic pain by a mechanism involving the alpha7 subtype of nAchRs, similar to the nonselective AR antagonist caffeine, taken as the reference compound. Along with the pharmacological evaluation, chemical stability of methyl 3-(((6-amino-3,5-dicyano-4-(furan-2-yl)pyridin-2-yl)sulfanyl)methyl)benzoate was assessed in plasma matrices (rat and human), and molecular modeling studies were carried out to better rationalize the available structure-activity relationships.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00106DOI Listing
August 2019

Functional characterization of a novel adenosine A receptor agonist on short-term plasticity and synaptic inhibition during oxygen and glucose deprivation in the rat CA1 hippocampus.

Brain Res Bull 2019 09 24;151:174-180. Epub 2019 May 24.

Department of Neuroscience, Psychology, Drug Research and Child Health, NEUROFARBA, Section of Pharmacology and Toxicology, University of Florence, Florence, Italy. Electronic address:

Adenosine is an endogenous neuromodulator exerting its biological functions via four receptor subtypes, A, A, A, and A. A receptors (ARs) are expressed at hippocampal level where they are known to inhibit paired pulse facilitation (PPF), whose reduction reflects an increase in presynaptic glutamate release. The effect of ARs on PPF is known to be sensitive not only to AR blockade but also to the AR antagonist DPCPX, indicating that it involves AR activation. In this study we provide the first functional characterization of the newly synthesized non-nucleoside like AR agonist P453, belonging to the amino-3,5-dicyanopyridine series. By extracellular electrophysiological recordings, we demonstrated that P453 mimicked the effect of the prototypical AR agonist BAY60-6583 in decreasing PPF at Schaffer collateral-CA1 synapses in rat acute hippocampal slices. This effect was prevented by two different AR antagonists, PSB603 and MRS1754, and by the AR antagonist DPCPX. We also investigated the functional role of AR during a 2 min of oxygen and glucose deprivation (OGD) insult, known to produce a reversible fEPSP inhibition due to adenosine AR activation. We found that P453 and BAY60-6583 significantly delayed the onset of fEPSP reduction induced by OGD and the effect was blocked by PSB603. We conclude that P453 is a functional AR agonist whose activation decreases PPF by increasing glutamate release at presynaptic terminals and delays AR-mediated fEPSP inhibition during a 2-minute OGD insult.
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http://dx.doi.org/10.1016/j.brainresbull.2019.05.018DOI Listing
September 2019

Novel 8-amino-1,2,4-triazolo[4,3-a]pyrazin-3-one derivatives as potent human adenosine A and A receptor antagonists. Evaluation of their protective effect against β-amyloid-induced neurotoxicity in SH-SY5Y cells.

Bioorg Chem 2019 06 16;87:380-394. Epub 2019 Mar 16.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy. Electronic address:

In this work, an enlarged series of 1,2,4-triazolo[4,3-a]pyrazin-3-ones was designed to target the human (h) A adenosine receptor (AR) or both hA and hA ARs. The novel 8-amino-1,2,4-triazolopyrazin-3-one derivatives 1-25 featured a phenyl or a benzyl pendant at position 2 while different aryl/heteroaryl substituents were placed at position 6. Two compounds (8 and 10) endowed with high affinity (K = 7.2 and 10.6 nM) and a complete selectivity for the hA AR were identified. Moreover, several derivatives possessed nanomolar affinity for both hA and hA ARs (both K < 20 nM) and different degrees of selectivity versus the hA AR. Two selected compounds (10 and 25) demonstrated ability in preventing β-amyloid peptide (25-35)-induced neurotoxicity in SH-SY5Y cells. Results of docking studies at the hA and hA AR crystal structures helped us to rationalize the observed affinity data and to highlight that the steric hindrance of the substituents at the 2- and 6-position of the bicyclic core affects the binding mode in the receptor cavity.
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http://dx.doi.org/10.1016/j.bioorg.2019.03.046DOI Listing
June 2019

Novel human adenosine receptor antagonists based on the 7-amino-thiazolo[5,4-d]pyrimidine scaffold. Structural investigations at the 2-, 5- and 7-positions to enhance affinity and tune selectivity.

Bioorg Med Chem Lett 2019 02 31;29(4):563-569. Epub 2018 Dec 31.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy.

This paper describes the synthesis of novel 7-amino-thiazolo[5,4-d]pyrimidines bearing different substituents at positions 2, 5 and 7 of the thiazolopyrimidine scaffold. The synthesized compounds 2-27 were evaluated in radioligand binding (A, A and A) and adenylyl cyclase activity (A and A) assays, in order to evaluate their affinity and potency at human adenosine receptor subtypes. The current study allowed us to support that affinity and selectivity of 7-amino-thiazolo[5,4-d]pyrimidine derivatives towards the adenosine receptor subtypes can be modulated by the nature of the groups attached at positions 2, 5 and 7 of the bicyclic scaffold. To rationalize the hypothetical binding mode of the newly synthesized compounds, we also performed docking calculations in human A, A and A structures.
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http://dx.doi.org/10.1016/j.bmcl.2018.12.062DOI Listing
February 2019

Structure-activity relationship studies and pharmacological characterization of N-heteroarylalkyl-substituted-2-(2-furanyl)thiazolo[5,4-d]pyrimidine-5,7-diamine-based derivatives as inverse agonists at human A adenosine receptor.

Eur J Med Chem 2018 Jul 9;155:552-561. Epub 2018 Jun 9.

Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara 17-19, 44121, Ferrara, Italy.

This paper describes the synthesis and characterization of N-(hetero)arylalkyl-substituted-thiazolo [5,4-d]pyrimidine-5,7-diamine derivatives (4-19) as novel human (h) A adenosine receptor (AR) inverse agonists. Competition binding and cyclic AMP assays indicate that the examined compounds behave as hA AR inverse agonists showing binding affinity values in the nanomolar or subnanomolar range. Notably, compounds 4, 5, 6 and 11 showed two affinity values for the hA ARs with the highest (KH) falling in the femtomolar range and the lowest (KL) of the nanomolar order. In addition, in cyclic AMP assays, compounds 4, 5, 6 and 11 exhibited potency (IC) values in the picomolar range. This study has confirmed that 2-(2-furanyl)thiazolo [5,4-d]pyrimidine-5,7-diamine-based derivatives represent a unique new class of hA AR inverse agonists.
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http://dx.doi.org/10.1016/j.ejmech.2018.06.020DOI Listing
July 2018

Identification of novel thiazolo[5,4-d]pyrimidine derivatives as human A and A adenosine receptor antagonists/inverse agonists.

Bioorg Med Chem 2018 07 31;26(12):3688-3695. Epub 2018 May 31.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy.

In this study a new set of thiazolo[5,4-d]pyrimidine derivatives was synthesized. These derivatives bear different substituents at positions 2 and 5 of the thiazolopyrimidine core while maintaining a free amino group at position-7. The new compounds were tested for their affinity and potency at human (h) A, A, A and A adenosine receptors expressed in CHO cells. The results reveal that the higher affinity of these new set of thiazolopyrimidines is toward the hA and hA adenosine receptors subtypes and is tuned by the substitution pattern at both the 2 and 5 positions of the thiazolopyrimidine nucleus. Functional studies evidenced that the compounds behaved as dual A/A antagonists/inverse agonists. Compound 3, bearing a 5-((2-methoxyphenyl) methylamino) group and a phenyl moiety at position 2, displayed the highest affinity (hA K = 10.2 nM; hA K = 4.72 nM) and behaved as a potent A/A antagonist/inverse agonist (hA IC = 13.4 nM; hA IC = 5.34 nM).
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http://dx.doi.org/10.1016/j.bmc.2018.05.048DOI Listing
July 2018

Development of novel pyridazinone-based adenosine receptor ligands.

Bioorg Med Chem Lett 2018 05 30;28(9):1484-1489. Epub 2018 Mar 30.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy.

With the aim of finding new adenosine receptor (AR) ligands, a preliminary investigation focusing on the thieno[2,3-d]pyridazin-5(4H)-one scaffold was undertaken. The synthesized compounds 1-11 were evaluated for their binding at hA, hA and hA ARs and efficacy at hA subtype in order to determine the affinity at the human adenosine receptor subtypes. Small structural changes on this scaffold highly influenced affinity; compound 5 (5-ethyl-7-(thiazol-2-yl)thieno[2,3-d]pyridazin-4(5H)-one) emerged as the best of this series. The simplicity of the synthetic process, the capability of the scaffold to be easily decorated, together with the predicted ADME properties confirm the role of these compounds as promising hits. A molecular docking investigation at the hAAR crystal structure was performed to rationalize the SARs of the herein reported thienopyridazinones.
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http://dx.doi.org/10.1016/j.bmcl.2018.03.086DOI Listing
May 2018

The aminopyridine-3,5-dicarbonitrile core for the design of new non-nucleoside-like agonists of the human adenosine A receptor.

Eur J Med Chem 2018 Apr 6;150:127-139. Epub 2018 Mar 6.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy.

A new series of amino-3,5-dicyanopyridines (3-28) as analogues of the adenosine hA receptor agonist BAY60-6583 (compound 1) was synthesized. All the compounds that interact with the hA adenosine receptor display EC values in the range 9-350 nM behaving as partial agonists, with the only exception being the 2-{[4-(4-acetamidophenyl)-6-amino-3,5-dicyanopyridin-2-yl]thio}acetamide (8) which shows a full agonist profile. Moreover, the 2-[(1H-imidazol-2-yl)methylthio)]-6-amino-4-(4-cyclopropylmethoxy-phenyl)pyridine-3,5-dicarbonitrile (15) turns out to be 3-fold more active than 1 although less selective. This result can be considered a real breakthrough due to the currently limited number of non-adenosine hA AR agonists reported in literature. To simulate the binding mode of nucleoside and non-nucleoside agonists at the hA AR, molecular docking studies were performed at homology models of this AR subtype developed by using two crystal structures of agonist-bound A AR as templates. These investigations allowed us to represent a hypothetical binding mode of hA receptor agonists belonging to the amino-3,5-dicyanopyridine series and to rationalize the observed SAR.
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http://dx.doi.org/10.1016/j.ejmech.2018.02.081DOI Listing
April 2018

Structural investigations on coumarins leading to chromeno[4,3-c]pyrazol-4-ones and pyrano[4,3-c]pyrazol-4-ones: New scaffolds for the design of the tumor-associated carbonic anhydrase isoforms IX and XII.

Eur J Med Chem 2018 Feb 12;146:47-59. Epub 2018 Jan 12.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy. Electronic address:

Human carbonic anhydrases (hCAs, EC 4.2.1.1) IX and XII are overexpressed in a wide variety of cancers and are considered available drug targets for anti-tumor therapy since their inhibition has been shown to reduce tumor growth and metastasis. A set of coumarin derivatives (1-10) and several 1-aryl and 2-aryl-substituted chromeno[4,3-c]pyrazol-4-ones (11-37) and pyrano[4,3-c]pyrazol-4-ones (38-39) were synthesized and tested against the tumor-associated hCAs IX and XII and the cytosolic isoforms hCAs I and II. Several compounds were potent (K < 41 nM) and selective inhibitors of the hCA IX (13, 14, 19, 21, 25, 31, 33, 37 and 39), some derivatives (6, 11 and 17) were active against both hCA IX and XII isoforms (K = 5.6-9.6 nM), while none were effective against the off-target cytosolic hCAs I and II. Some selected inhibitors (6, 11, 13, 19, 21, 25, 31 and 39) showed activity as antiproliferative agents on HT-29 colon cancer cell lines both in normoxic and hypoxic conditions. This finding led us to hypothesize for these derivatives more than one mechanism of action, involving hCAs IX and XII inhibition in hypoxia and other not identified target(s) in normoxia.
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http://dx.doi.org/10.1016/j.ejmech.2018.01.033DOI Listing
February 2018

Inhibition of A Adenosine Receptor Signaling in Cancer Cells Proliferation by the Novel Antagonist TP455.

Front Pharmacol 2017 1;8:888. Epub 2017 Dec 1.

Department of Medical Sciences, Pharmacology Section, University of Ferrara, Ferrara, Italy.

Several evidences indicate that the ubiquitous nucleoside adenosine, acting through A, A, A, and A receptor (AR) subtypes, plays crucial roles in tumor development. Adenosine has contrasting effects on cell proliferation depending on the engagement of different receptor subtypes in various tumors. The involvement of AARs in human A375 melanoma, as well as in human A549 lung and rat MRMT1 breast carcinoma proliferation has been evaluated in view of the availability of a novel AAR antagonist, with high affinity and selectivity, named as 2-(2-furanyl)-N-(2-methoxybenzyl)[1,3]thiazolo[5,4-d]pyrimidine-5,7-diammine (TP455). Specifically, the signaling pathways triggered in the cancer cells of different origin and the antagonist effect of TP455 were investigated. The AAR protein expression was evaluated through receptor binding assays. Furthermore, the effect of AAR activation on cell proliferation at 24, 48 and 72 hours was studied. The selective AAR agonist 2--(2-carboxyethyl)phenethylamino-5'--ethylcarboxamidoadenosine hydrochloride (CGS21680), concentration-dependently induced cell proliferation in A375, A549, and MRMT1 cancer cells and the effect was potently antagonized by the AAR antagonist TP455, as well as by the reference AAR blocker 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385). As for the signaling pathway recruited in this response we demonstrated that, by using the specific inhibitors of signal transduction pathways, the effect of AAR stimulation was induced through phospholipase C (PLC) and protein kinase C-delta (PKC-δ). In addition, we evaluated, through the AlphaScreen SureFire phospho(p) protein assay, the kinases enrolled by AAR to stimulate cell proliferation and we found the involvement of protein kinase B (AKT), extracellular regulated kinases (ERK1/2), and c-Jun N-terminal kinases (JNKs). Indeed, we demonstrated that the CGS21680 stimulatory effect on kinases was strongly reduced in the presence of the new potent compound TP455, as well as by ZM241385, confirming the role of the AAR. In conclusion, the AAR activation stimulates proliferation of A375, A549, and MRMT1 cancer cells and importantly TP455 reveals its capability to counteract this effect, suggesting selective AAR antagonists as potential new therapeutics.
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http://dx.doi.org/10.3389/fphar.2017.00888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716981PMC
December 2017

3-Hydroxy-1H-quinazoline-2,4-dione as a New Scaffold To Develop Potent and Selective Inhibitors of the Tumor-Associated Carbonic Anhydrases IX and XII.

J Med Chem 2017 07 11;60(14):6428-6439. Epub 2017 Jul 11.

Sezione di Farmaceutica e Nutraceutica, Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Università degli Studi di Firenze , Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.

In this paper, we describe the discovery of the 3-hydroxyquinazoline-2,4-dione as a useful scaffold to obtain potent inhibitors of the tumor-associated human carbonic anhydrases (hCAs) IX and XII. A set of derivatives (1-29), bearing different substituents on the fused benzo ring (Cl, NO, NH, CF, ureido, amido, heterocycles), were synthesized, and several of them showed nanomolar activity in inhibiting the hCA IX and XII isoforms, while they were ineffective against the cytosolic enzymes hCAs I and II. Some selected compounds were tested for their antiproliferative activity against HT-29 colon cancer cell lines. After 48 h of treatment with the lower dose (30 μM), derivatives 12, 14, 15, and 19 were significantly active, inducing a mortality by about 50% in both normoxia and hypoxia. This finding led us to hypothesize for these compounds more than one mechanism of action involving both CAs IX and XII and other not yet identified target(s).
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http://dx.doi.org/10.1021/acs.jmedchem.7b00766DOI Listing
July 2017

The 1,2,4-Triazolo[4,3-a]pyrazin-3-one as a Versatile Scaffold for the Design of Potent Adenosine Human Receptor Antagonists. Structural Investigations to Target the A Receptor Subtype.

J Med Chem 2017 07 16;60(13):5772-5790. Epub 2017 Jun 16.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze , Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.

In this work, we describe the identification of the 1,2,4-triazolo[4,3-a]pyrazin-3-one as a new versatile scaffold for the development of adenosine human (h) receptor antagonists. The new chemotype ensued from a molecular simplification approach applied to our previously reported 1,2,4-triazolo[4,3-a]quinoxalin-1-one series. Hence, a set of novel 8-amino-2-aryl-1,2,4-triazolopyrazin-3-one derivatives, featured by different substituents on the 2-phenyl ring (R) and at position 6 (R), was synthesized with the main purpose of targeting the hA adenosine receptor (AR). Several compounds possessed nanomolar affinity for the hA AR (K = 2.9-10 nM) and some, very interestingly, also showed high selectivity for the target. One selected potent hA AR antagonist (12, R = H, R = 4-methoxyphenyl) demonstrated some ability to counteract MPP-induced neurotoxicity in cultured human neuroblastoma SH-SY5Y cells, a widely used in vitro Parkinson's disease model. Docking studies at hAR structures were performed to rationalize the observed affinity data.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00457DOI Listing
July 2017

The role of 5-arylalkylamino- and 5-piperazino- moieties on the 7-aminopyrazolo[4,3-d]pyrimidine core in affecting adenosine A and A receptor affinity and selectivity profiles.

J Enzyme Inhib Med Chem 2017 Dec;32(1):248-263

a Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università di Firenze , Sesto Fiorentino , Italy.

New 7-amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives, substituted at the 5-position with aryl(alkyl)amino- and 4-substituted-piperazin-1-yl- moieties, were synthesized with the aim of targeting human (h) adenosine A and/or A receptor subtypes. On the whole, the novel derivatives 1-24 shared scarce or no affinities for the off-target hA and hA ARs. The 5-(4-hydroxyphenethylamino)- derivative 12 showed both good affinity (K = 150 nM) and the best selectivity for the hA AR while the 5-benzylamino-substituted 5 displayed the best combined hA (K = 123 nM) and A AR affinity (K = 25 nM). The 5-phenethylamino moiety (compound 6) achieved nanomolar affinity (K = 11 nM) and good selectivity for the hA AR. The 5-(N-substituted-piperazin-1-yl) derivatives 15-24 bind the hA AR subtype with affinities falling in the high nanomolar range. A structure-based molecular modeling study was conducted to rationalize the experimental binding data from a molecular point of view using both molecular docking studies and Interaction Energy Fingerprints (IEFs) analysis.[Formula: see text].
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http://dx.doi.org/10.1080/14756366.2016.1247060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009979PMC
December 2017

Design, Synthesis, and Pharmacological Characterization of 2-(2-Furanyl)thiazolo[5,4-d]pyrimidine-5,7-diamine Derivatives: New Highly Potent A Adenosine Receptor Inverse Agonists with Antinociceptive Activity.

J Med Chem 2016 12 29;59(23):10564-10576. Epub 2016 Nov 29.

Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara , via Fossato di Mortara 17-19, 44121, Ferrara, Italy.

In this study, we describe the design and synthesis of new N-substituted-2-(2-furanyl) thiazolo[5,4-d]pyrimidine-5,7-diamines (2-18) and their pharmacological characterization as A adenosine receptor (AR) antagonists by using in vitro and in vivo assays. In competition binding experiments two derivatives (13 and 14) emerged as outstanding ligands showing two different affinity values (KH and KL) for the hA receptor with the high affinity KH value in the femtomolar range. The in vitro functional activity assays, performed by using cyclic AMP experiments, assessed that they behave as potent inverse agonists at the hA AR. Compounds 13 and 14 were evaluated for their antinociceptive activity in acute experimental models of pain showing an effect equal to or greater than that of morphine. Overall, these novel inverse agonists might represent potential drug candidates for an alternative approach to the management of pain.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01068DOI Listing
December 2016

Imidazo[1,2-a]pyrazin-8-amine core for the design of new adenosine receptor antagonists: Structural exploration to target the A and A subtypes.

Eur J Med Chem 2017 Jan 26;125:611-628. Epub 2016 Sep 26.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sez. Farmaceutica e Nutraceutica, Universita' degli Studi di Firenze, Via Ugo Schiff 6, 50019, Sesto Fiorentino (FI), Italy.

The imidazo[1,2-a]pyrazine ring system has been chosen as a new decorable core skeleton for the design of novel adenosine receptor (AR) antagonists targeting either the human (h) A or the hA receptor subtype. The N-(hetero)arylcarboxyamido substituted compounds 4-14 and 21-30, bearing a 6-phenyl moiety or not, respectively, show good hA receptor affinity and selectivity versus the other ARs. In contrast, the 8-amino-6-(hetero)aryl substituted derivatives designed for targeting the hA receptor subtype (compounds 31-38) and also the 6-phenyl analogues 18-20 do not bind the hA AR, or show hA or balanced hA/hA AR affinity in the micromolar range. Molecular docking of the new hA antagonists was carried out to depict their hypothetical binding mode to our refined model of the hA receptor. Some derivatives were evaluated for their fluorescent potentiality and showed some fluorescent emission properties. One of the most active hA antagonists herein reported, i.e. the 2,6-diphenyl-8-(3-pyridoylamino)imidazo[1,2-a]pyrazine 29, tested in a rat model of cerebral ischemia, delayed the occurrence of anoxic depolarization caused by oxygen and glucose deprivation in the hippocampus and allowed disrupted synaptic activity to recover.
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http://dx.doi.org/10.1016/j.ejmech.2016.09.076DOI Listing
January 2017

Exploring the 2- and 5-positions of the pyrazolo[4,3-d]pyrimidin-7-amino scaffold to target human A1 and A2A adenosine receptors.

Bioorg Med Chem 2016 06 23;24(12):2794-808. Epub 2016 Apr 23.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy. Electronic address:

A new series of 7-aminopyrazolo[4,3-d]pyrimidine derivatives (1-31) were synthesized to evaluate some structural modifications at the 2- and 5-positions aimed at shifting affinity towards the human (h) A2A adenosine receptor (AR) or both hA2A and hA1 ARs. The most active compounds were those featured by a 2-furyl or 5-methylfuran-2-yl moiety at position 5, combined with a benzyl or a substituted-benzyl group at position 2. Several of these derivatives (22-31) displayed nanomolar affinity for the hA2A AR (Ki=3.62-57nM) and slightly lower for the hA1 ARs, thus showing different degrees (3-22 fold) of hA2A versus hA1 selectivity. In particular, the 2-(2-methoxybenzyl)-5-(5-methylfuran-2-yl) derivative 25 possessed the highest hA2A and hA1 AR affinities (Ki=3.62nM and 18nM, respectively) and behaved as potent antagonist at both these receptors (cAMP assays). Its 2-(2-hydroxybenzyl) analog 26 also showed a high affinity for the hA2A AR (Ki=5.26nM) and was 22-fold selective versus the hA1 subtype. Molecular docking investigations performed at the hA2A AR crystal structure and at a homology model of the hA1 AR allowed us to represent the hypothetical binding mode of our derivatives and to rationalize the observed SARs.
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http://dx.doi.org/10.1016/j.bmc.2016.04.048DOI Listing
June 2016

Structural refinement of pyrazolo[4,3-d]pyrimidine derivatives to obtain highly potent and selective antagonists for the human A3 adenosine receptor.

Eur J Med Chem 2016 Jan 17;108:117-133. Epub 2015 Nov 17.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e salute del Bambino, sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy. Electronic address:

In previous research, we identified some 7-oxo- and 7-acylamino-substituted pyrazolo[4,3-d]pyrimidine derivatives as potent and selective human (h) A3 adenosine receptor (AR) antagonists. Herein we report on the structural refinement of this class of antagonists aimed at achieving improved receptor-ligand recognition. Hence, substituents with different steric bulk, flexibility and lipophilicity (Me, Ar, heteroaryl, CH2Ph) were introduced at the 5- and 2-positions of the bicyclic scaffold of both the 7-oxo and 7-amino derivatives, and acyl residues were appended on the 7-amino group of the latter. All the 2-phenylpyrazolo[4,3-d]pyrimidin-7-amines and 7-acylamines bearing a 4-methoxyphenyl- or a 2-thienyl group at the 5-position showed high hA3 affinity and selectivity. In particular, the 2-phenyl-5-(2-thienyl)-pyrazolo[4,3-d]pyrimidin-7-(4-methoxybenzoyl)amine 25 (Ki = 0.027 nM) is one of the most potent and selective hA3 antagonists reported so far. By using an in silico receptor-driven approach the obtained binding data were rationalized and the molecular bases of the observed hA3 AR affinities were critically described.
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http://dx.doi.org/10.1016/j.ejmech.2015.11.015DOI Listing
January 2016

Exploring the 7-oxo-thiazolo[5,4-d]pyrimidine core for the design of new human adenosine A3 receptor antagonists. Synthesis, molecular modeling studies and pharmacological evaluation.

Eur J Med Chem 2015 4;96:105-21. Epub 2015 Apr 4.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Universita' di Firenze, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy.

A new series of 5-methyl-thiazolo[5,4-d]pyrimidine-7-ones bearing different substituents at position 2 (aryl, heteroaryl and arylamino groups) was synthesized and evaluated in radioligand binding assays to determine their affinities at the human (h) A1, A2A, and A3 adenosine receptors (ARs). Efficacy at the hA(2B) and antagonism of selected ligands at the hA3 were also assessed through cAMP experiments. Some of the new derivatives exhibited good to high hA3AR affinity and selectivity versus all the other AR subtypes. Compound 2-(4-chlorophenyl)-5-methyl-thiazolo[5,4-d]pyrimidine-7-one 4 was found to be the most potent and selective ligand of the series (K(I) hA3 = 18 nM). Molecular docking studies of the reported derivatives were carried out to depict their hypothetical binding mode in our hA3 receptor model.
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http://dx.doi.org/10.1016/j.ejmech.2015.04.010DOI Listing
April 2016

1,2,4-triazolo[1,5-a]quinoxaline derivatives and their simplified analogues as adenosine A₃ receptor antagonists. Synthesis, structure-affinity relationships and molecular modeling studies.

Bioorg Med Chem 2015 Jan 27;23(1):9-21. Epub 2014 Nov 27.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università di Firenze, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy.

The 1,2,4-triazolo[1,5-a]quinoxaline (TQX) scaffold was extensively investigated in our previously reported studies and recently, our attention was focused at position 5 of the tricyclic nucleus where different acyl and carboxylate moieties were introduced (compounds 2-15). This study produced some interesting compounds endowed with good hA3 receptor affinity and selectivity. In addition, to find new insights about the structural requirements for hA3 receptor-ligand interaction, the tricyclic TQX ring was destroyed yielding some 1,2,4-triazole derivatives (compounds 16-23). These simplified compounds, though maintaining the crucial structural requirements for adenosine receptor-ligand interaction, have a very low hA3 adenosine receptor affinity, the only exception being compound 23 (1-[3-(4-methoxyphenyl)-1-phenyl-1H-1,2,4-triazol-5-yl]-3-phenylurea) endowed with a Ki value in the micro-molar range and high hA3 selectivity versus both hA1 and hA2A AR subtypes. Evaluation of the side products obtained in the herein reported synthetic pathways led to the identification of some new triazolo[1,5-a]quinoxalines as hA3AR antagonists (compounds 24-27). These derivatives, though lacking the classical structural requirements for the anchoring at the hA3 receptor site, show high hA3 affinity and in some case selectivity versus hA1 and hA2A subtypes. Molecular docking of the herein reported tricyclic and simplified derivatives was carried out to depict their hypothetical binding mode to our model of hA3 receptor.
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http://dx.doi.org/10.1016/j.bmc.2014.11.033DOI Listing
January 2015

1,2,4-Benzothiadiazine-1,1-dioxide derivatives as ionotropic glutamate receptor ligands: synthesis and structure-activity relationships.

Arch Pharm (Weinheim) 2014 Nov 10;347(11):777-85. Epub 2014 Sep 10.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università di Firenze, Sesto Fiorentino, Italy.

Ionotropic glutamate receptor (iGluR) modulators, specially AMPA receptor antagonists, are potential tools for numerous therapeutic applications in neurological disorders, including Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, epilepsy, chronic pain, and neuropathology ensuing from cerebral ischemia or cardiac arrest. In this work, the synthesis and binding affinities at the Gly/NMDA, AMPA, and kainic acid (KA) receptors of a new series of 1,2,4-benzothiadiazine-1,1-dioxide derivatives are reported. The results show that 1,2,4-benzothiadiazine-1,1-dioxide is a new scaffold for obtaining iGluR ligands. Moreover, this work has led us to the 7-(3-formylpyrrol-1-yl)-6-trifluoromethyl substituted compound 7, which displays the highest AMPA receptor affinity and high selectivity versus the Gly/NMDA (90-fold) and KA (46-fold) receptors.
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http://dx.doi.org/10.1002/ardp.201400192DOI Listing
November 2014

7-Amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives: structural investigations at the 5-position to target human A₁ and A(2A) adenosine receptors. Molecular modeling and pharmacological studies.

Eur J Med Chem 2014 Sep 19;84:614-27. Epub 2014 Jul 19.

Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131 Padova, Italy. Electronic address:

In previous research, several 7-amino-2-arylpyrazolo[4,3-d]pyrimidine derivatives were identified as highly potent and selective antagonists at the human A3 adenosine receptor. Structure-activity relationship studies highlighted that affinity and selectivity depended on the nature of the substituents at the 5- and 7-positions of the pyrazolo[4,3-d]pyrimidine scaffold. In particular, small lipophilic residues at the 5-position and a free amino group at position 7 afforded compounds able to bind all four human (h) adenosine receptors. Hence, to shift affinity toward the hA1 and/or hA(2A) subtypes, alkyl and arylalkyl chains of different length were appended at position 5 of the 2-phenylpyrazolo[4,3-d]pyrimidin-7-amine. Among the new compounds, a dual hA1/hA(2A) receptor antagonist was identified, namely the 5-(3-phenylpropyl) derivative 25, which shows high affinity both at human A1 (K(i) = 5.31 nM) and A(2A) (K(i) = 55 nM) receptors. We also obtained some potent and selective antagonists for the A1 receptor, such as the 5-(3-arylpropyl)-substituted compounds 26-31, whose affinities fall in the low nanomolar range (K(i) = 0.15-18 nM). Through an in silico receptor-driven approach, the obtained binding data were rationalized and the molecular bases of the hA1 and hA(2A) AR affinity and selectivity of derivatives 25-31 are explained.
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http://dx.doi.org/10.1016/j.ejmech.2014.07.060DOI Listing
September 2014

2-Arylpyrazolo[4,3-d]pyrimidin-7-amino derivatives as new potent and selective human A3 adenosine receptor antagonists. Molecular modeling studies and pharmacological evaluation.

J Med Chem 2013 Mar 7;56(6):2256-69. Epub 2013 Mar 7.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy.

On the basis of our previously reported 2-arylpyrazolo[4,3-d]pyrimidin-7-ones, a set of 2-arylpyrazolo[4,3-d]pyrimidin-7-amines were designed as new human (h) A3 adenosine receptor (AR) antagonists. Lipophilic groups with different steric bulk were introduced at the 5-position of the bicyclic scaffold (R5 = Me, Ph, CH2Ph), and different acyl and carbamoyl moieties (R7) were appended on the 7-amino group, as well as a para-methoxy group inserted on the 2-phenyl ring. The presence of acyl groups turned out to be of paramount importance for an efficient and selective binding at the hA3 AR. In fact, most of the 7-acylamino derivatives showed low nanomolar affinity (Ki = 2.5-45 nM) and high selectivity toward this receptor. A few selected pyrazolo[4,3-d]pyrimidin-7-amides were effective in counteracting oxaliplatin-induced apoptosis in rat astrocyte cell cultures, an in vitro model of neurotoxicity. Through an in silico receptor-driven approach the obtained binding data were rationalized and the molecular bases of the observed hA3 AR affinity and hA3 versus hA2A AR selectivity were explained.
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http://dx.doi.org/10.1021/jm400068eDOI Listing
March 2013