4-Amido-2-aryl-1,2,4-triazolo[4,3-<i>a</i>]quinoxalin-1-ones as New Potent and Selective Human A<sub>3</sub> Adenosine Receptor Antagonists. Synthesis, Pharmacological Evaluation, and Ligand−Receptor Modeling Studies

Lenzi, Ombretta; Colotta, Vittoria; Catarzi, Daniela; Varano, Flavia; Filacchioni, Guido; Martini, Claudia; Trincavelli, Maria Letizia; Ciampi, Osele; Varani, Katia; Marighetti, Federico; Morizzo, Erika; Moro, Stefano

doi:10.1021/jm060373w

Cited by 55 publications

(76 citation statements)

References 36 publications

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“…Interesting studies performed in the last decade by Colotta and coworkers highlighted that the 1,2,4-triazolo[4,3- a ]quinoxalin-1-one moiety is an attractive scaffold for obtaining potent and selective hA 3 AR antagonists (Colotta et al 2004; Lenzi et al 2006). Intensive efforts in the chemical synthesis of compounds based on the systematic substitution of the 2, 4 and 6 positions of the tricyclic template, along with molecular modeling investigations performed to rationalize the experimental SAR findings, led to the identification of optimal structural requirements for A 3 AR affinity and selectivity.…”

Section: A3ar Antagonistsmentioning

confidence: 99%

Medicinal Chemistry of the A3 Adenosine Receptor: Agonists, Antagonists, and Receptor Engineering

Jacobson

Klutz

Tosh

et al. 2009

Adenosine Receptors in Health and Disease

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A3 adenosine receptor (A3AR) ligands have been modified to optimize their interaction with the A3AR. Most of these modifications have been made to the N6 and C2 positions of adenine as well as the ribose moiety, and using a combination of these substitutions leads to the most efficacious, selective, and potent ligands. A3AR agonists such as IB-MECA and Cl-IB-MECA are now advancing into Phase II clinical trials for treatments targeting diseases such as cancer, arthritis, and psoriasis. Also, a wide number of compounds exerting high potency and selectivity in antagonizing the human (h)A3AR have been discovered. These molecules are generally characterized by a notable structural diversity, taking into account that aromatic nitrogen-containing monocyclic (thiazoles and thiadiazoles), bicyclic (isoquinoline, quinozalines, (aza)adenines), tricyclic systems (pyrazoloquinolines, triazoloquinoxalines, pyrazolotriazolopyrimidines, triazolopurines, tricyclic xanthines) and nucleoside derivatives have been identified as potent and selective A3AR antagonists. Probably due to the “enigmatic” physiological role of A3AR, whose activation may produce opposite effects (for example, concerning tissue protection in inflammatory and cancer cells) and may produce effects that are species dependent, only a few molecules have reached preclinical investigation. Indeed, the most advanced A3AR antagonists remain in preclinical testing. Among the antagonists described above, compound OT-7999 is expected to enter clinical trials for the treatment of glaucoma, while several thiazole derivatives are in development as antiallergic, antiasthmatic and/or antiinflammatory drugs.

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Section: A3ar Antagonistsmentioning

confidence: 99%

Medicinal Chemistry of the A3 Adenosine Receptor: Agonists, Antagonists, and Receptor Engineering

Jacobson

Klutz

Tosh

et al. 2009

Adenosine Receptors in Health and Disease

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“…[17] For our second goal, we performed molecular modeling studies of the newly synthesized A 3 antagonist 10 and a published hA 3 receptor model, [18] using docking and molecular dynamic simulations techniques. It should be mentioned that molecular modeling of the A 3 receptor is being heavily investigated with at least three aims: to perform a pharmacophore analysis to obtain new lead compounds; [19] to rationalize the increase in potency and/or selectivity of already synthesized compounds; [20] or, as performed by Kim et al, [21] to get a better understanding of receptor activation. Our aim is clearly in the second category, using compound 10 as the ligand and the described model of the transmembrane domain of the hA 3 as the receptor.…”

Section: Introductionmentioning

confidence: 99%

Selective Human Adenosine A₃ Antagonists based on Pyrido[2,1‐f]purine‐2,4‐diones: Novel Features of hA₃ Antagonist Binding

et al. 2008

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Based on our previous results on the potent antagonist effect of 1H,3H-pyrido[2,1-f]purine-2,4-diones at the human A(3) adenosine receptor, new series of this family of compounds have been synthesized and evaluated in radioligand binding studies against the human A(1), A(2A), A(2B), and A(3) receptors. A remarkable improvement in potency, and most noticeable, in selectivity has been achieved, as exemplified by the 3-cyclopropylmethyl-8-methoxy-1-(4-methylbenzyl)-1H,3H-pyrido[2,1-f]purine-2,4-dione (10) that combines a very high affinity at hA(3) (K(i)=2.24 nM), with lack of affinity for the A(1), A(2A), and A(2B) receptors. On the basis of the published hA(3) receptor model (PDB 1OEA), molecular modeling studies, including molecular dynamics (MD) simulations, have been performed to depict the binding mode of the 1 H,3H-pyrido[2,1-f]purine-2,4-diones and to justify the selectivity against the other adenosine receptors. These studies have led to novel features of the cavity where our antagonists are bound so that the cavity is lined by the hydrogen-bonded Gln 167-Asn 250 pair and by the highly conserved Phe 168.

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“…16 Various heterocyclic classes have been identified as promising leads for A 3 AR antagonists, among them 1,4-dihydropyridines, pyridines, deazaadenines, pyrazolopyrimidines, adenines, and 1,2,4-triazolo [ 4,3-a]quinoxalin-1-ones. 4,7,17,18 However, the A 3 AR, more than other AR subtypes, is amenable to the design of nucleosidebased antagonists. The efficacy of nucleoside derivatives in activation of the A 3 AR is particularly sensitive to molecular substitution of the ligand.…”

Section: Introductionmentioning

confidence: 99%

2-Triazole-Substituted Adenosines: A New Class of Selective A₃Adenosine Receptor Agonists, Partial Agonists, and Antagonists

et al. 2006

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Abstract"Click chemistry" was explored to synthesize two series of 2-(1,2,3-triazolyl)adenosine derivatives (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Binding affinity at the human A 1 , A 2A , and A 3 ARs (adenosine receptors) and relative efficacy at the A 3 AR were determined. Some triazol-1-yl analogues showed A 3 AR affinity in the low nanomolar range, a high ratio of A 3 /A 2A selectivity, and a moderate-to-high A 3 /A 1 ratio. The 1,2,3-triazol-4-yl regiomers typically showed decreased A 3 AR affinity. Sterically demanding groups at the adenine C2 position tended to reduce relative A 3 AR efficacy. Thus, several 5′-OH derivatives appeared to be selective A 3 AR antagonists, i.e., 10, with 260-fold binding selectivity in comparison to the A 1 AR and displaying a characteristic docking mode in an A 3 AR model. The corresponding 5′-ethyluronamide analogues generally showed increased A 3 AR affinity and behaved as full agonists, i.e., 17, with 910-fold A 3 /A 1 selectivity. Thus, N 6 -substituted 2-(1,2,3-triazolyl)-adenosine analogues constitute a novel class of highly potent and selective nucleosidebased A 3 AR antagonists, partial agonists, and agonists.

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4-Amido-2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-ones as New Potent and Selective Human A₃ Adenosine Receptor Antagonists. Synthesis, Pharmacological Evaluation, and Ligand−Receptor Modeling Studies

Cited by 55 publications

References 36 publications

Medicinal Chemistry of the A3 Adenosine Receptor: Agonists, Antagonists, and Receptor Engineering

Medicinal Chemistry of the A3 Adenosine Receptor: Agonists, Antagonists, and Receptor Engineering

Selective Human Adenosine A₃ Antagonists based on Pyrido[2,1‐f]purine‐2,4‐diones: Novel Features of hA₃ Antagonist Binding

2-Triazole-Substituted Adenosines: A New Class of Selective A₃Adenosine Receptor Agonists, Partial Agonists, and Antagonists

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4-Amido-2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-ones as New Potent and Selective Human A3 Adenosine Receptor Antagonists. Synthesis, Pharmacological Evaluation, and Ligand−Receptor Modeling Studies

Cited by 55 publications

References 36 publications

Medicinal Chemistry of the A3 Adenosine Receptor: Agonists, Antagonists, and Receptor Engineering

Medicinal Chemistry of the A3 Adenosine Receptor: Agonists, Antagonists, and Receptor Engineering

Selective Human Adenosine A3 Antagonists based on Pyrido[2,1‐f]purine‐2,4‐diones: Novel Features of hA3 Antagonist Binding

2-Triazole-Substituted Adenosines: A New Class of Selective A3Adenosine Receptor Agonists, Partial Agonists, and Antagonists

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4-Amido-2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-ones as New Potent and Selective Human A₃ Adenosine Receptor Antagonists. Synthesis, Pharmacological Evaluation, and Ligand−Receptor Modeling Studies

Selective Human Adenosine A₃ Antagonists based on Pyrido[2,1‐f]purine‐2,4‐diones: Novel Features of hA₃ Antagonist Binding

2-Triazole-Substituted Adenosines: A New Class of Selective A₃Adenosine Receptor Agonists, Partial Agonists, and Antagonists