Structure–activity relationship studies of a new series of imidazo[2,1-f]purinones as potent and selective A3 adenosine receptor antagonists

Baraldi, Pier Giovanni; Preti, Delia; Tabrizi, Mojgan Aghazadeh; Romagnoli, Romeo; Saponaro, Giulia; Baraldi, Stefania; Botta, Maurizio; Bernardini, Cesare; Tafi, Andrea; Tuccinardi, Tiziano

doi:10.1016/j.bmc.2008.10.049

Cited by 14 publications

(26 citation statements)

References 44 publications

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“…Another contour map around the central scaffold substantiated the importance of π–π interactions with His95. The contour maps of the N 2 = and O probes at the 1‐position were coherent with that of the CH 3 probe, which inferred that this region should possess a lipophilic characteristic in order to improve the hA 3 AR affinity …”

Section: Molecular Modeling On Ha3ar and Its Ligandsmentioning

confidence: 68%

“…Better results were obtained with the cyclization of positions 7 and 8 of the purine nucleus, as represented by the pyridopurine‐2,4‐dione derivative (compound 101 , K i hA 3 AR = 4.0 nM), while further incorporation of an 8‐methoxy group enhanced the selectivity against other ARs (compound 102 , K i hA 3 AR = 2.2 nM) . Similarly, incorporation of an imidazole or a pyrrole ring at the same positions (7 and 8) of the xanthine scaffold gave rise to a new series of derivatives (compound 103 , K i hA 3 AR = 3.5 nM, and compound 104 , K i hA 3 AR = 0.8 nM), which were highly potent and selective hA 3 AR antagonists . In this work, researchers investigated also the effect of substitutions on the cycle constrained between positions 7 and 8, indicating that only small alkyl groups were permitted.…”

Section: Medicinal Chemistry Of A3ar Ligandsmentioning

confidence: 99%

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The A₃ adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches

Cheong

Federico

Venkatesan

et al. 2011

Medicinal Research Reviews

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Adenosine is an ubiquitous local modulator that regulates various physiological and pathological functions by stimulating four membrane receptors, namely A(1), A(2A), A(2B), and A(3). Among these G protein-coupled receptors, the A(3) subtype is found mainly in the lung, liver, heart, eyes, and brain in our body. It has been associated with cerebroprotection and cardioprotection, as well as modulation of cellular growth upon its selective activation. On the other hand, its inhibition by selective antagonists has been reported to be potentially useful in the treatment of pathological conditions including glaucoma, inflammatory diseases, and cancer. In this review, we focused on the pharmacology and the therapeutic implications of the human (h)A(3) adenosine receptor (AR), together with an overview on the progress of hA(3) AR agonists, antagonists, allosteric modulators, and radioligands, as well as on the recent advances pertaining to the computational approaches (e.g., quantitative structure-activity relationships, homology modeling, molecular docking, and molecular dynamics simulations) applied to the modeling of hA(3) AR and drug design.

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Section: Molecular Modeling On Ha3ar and Its Ligandsmentioning

confidence: 68%

Section: Medicinal Chemistry Of A3ar Ligandsmentioning

confidence: 99%

The A₃ adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches

Cheong

Federico

Venkatesan

et al. 2011

Medicinal Research Reviews

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show abstract

“…Rigorous research efforts were made on this scaffold in order to obtain potent A 2A ‐ and A 3 AR antagonists . A series of PTP derivatives (MRE series) reported by Baraldi's group were obtained by the structure–activity optimization based on the introduction of different substituents at the 5, 7, 8, and 9 positions . The N 7 ‐substituted derivatives proved to be predominantly hA 2A AR antagonists, while the combination of a small alkyl chain at the N 8 ‐pyrazole position with a (substituted)phenylcarbamoyl chain at the N 5 ‐position led to potent and selective hA 3 AR antagonists.…”

Section: Medicinal Chemistry Of the A3 Adenosine Receptormentioning

confidence: 99%

A₃ Adenosine Receptors as Modulators of Inflammation: From Medicinal Chemistry to Therapy

Jacobson

Merighi

Varani

et al. 2017

Medicinal Research Reviews

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123

181

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The A adenosine receptor (A AR) subtype is a novel, promising therapeutic target for inflammatory diseases, such as rheumatoid arthritis (RA) and psoriasis, as well as liver cancer. A AR is coupled to inhibition of adenylyl cyclase and regulation of mitogen-activated protein kinase (MAPK) pathways, leading to modulation of transcription. Furthermore, A AR affects functions of almost all immune cells and the proliferation of cancer cells. Numerous A AR agonists, partial agonists, antagonists, and allosteric modulators have been reported, and their structure-activity relationships (SARs) have been studied culminating in the development of potent and selective molecules with drug-like characteristics. The efficacy of nucleoside agonists may be suppressed to produce antagonists, by structural modification of the ribose moiety. Diverse classes of heterocycles have been discovered as selective A AR blockers, although with large species differences. Thus, as a result of intense basic research efforts, the outlook for development of A AR modulators for human therapeutics is encouraging. Two prototypical selective agonists, N6-(3-Iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA; CF101) and 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA; CF102), have progressed to advanced clinical trials. They were found safe and well tolerated in all preclinical and human clinical studies and showed promising results, particularly in psoriasis and RA, where the A AR is both a promising therapeutic target and a biologically predictive marker, suggesting a personalized medicine approach. Targeting the A AR may pave the way for safe and efficacious treatments for patient populations affected by inflammatory diseases, cancer, and other conditions.

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“…Another intriguing application has been reported by Michielan et al who took advantage of linear and nonlinear 3D QSAR approaches for the optimization of pyrazolo-triazolo-pyrimidines as human A 2A antagonists [51]. Concerning studies on A 3 AR ligands, a successful 3D QSAR application has been reported by Moro et al to optimize a series of pyrazolotriazolo-pyrimidines as human A 3 antagonists [52,58].…”

Section: Discussionmentioning

confidence: 95%

“…Extensive SAR studies have been performed by Baraldi et al on a series of imidazo[2,1-f]purinones in which the effect of different kinds of substitutions at the 1-, 3-, and 8 positions was evaluated [58].…”

Section: D Qsar Applicationsmentioning

confidence: 99%

Pharmacophoric Models and 3D QSAR Studies of the Adenosine Receptor Ligands

Tintori¹,

Manetti²,

Botta

2010

CTMC

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Computational methodologies are used to increase the efficiency of drug discovery process by rendering the design of new drug candidates more rapid and cost-efficient. In silico techniques can be divided in two main groups. Structure-based drug design procedures can be applied (such as docking simulations) if the target is known from experimental (i.e., X-ray crystallographic studies, NMR studies) or theoretical sources (receptor structure built by homology modeling techniques). Otherwise, ligand-based drug design methods can be used (e.g., QSAR or 3D QSAR models, pharmacophoric models) based on the analysis of a number of ligands known to act with a common mechanism of action. Adenosine receptors (ARs) are a family of G-protein coupled receptors (GPCRs) of great interest as targets for therapeutic intervention. Due partly to the lack of reliable adenosine receptor structures, ligand-based drug discovery methods remain the major computational molecular modeling approach applied in the research of new AR ligands. The scope of this review is to summarize the results on pharmacophoric models and 3D QSAR studies concerning AR ligands. In particular, the review will focus on the use of such ligand-based computational techniques for the identification of new AR ligands and/or for their optimization.

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Structure–activity relationship studies of a new series of imidazo[2,1-f]purinones as potent and selective A3 adenosine receptor antagonists

Cited by 14 publications

References 44 publications

The A₃ adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches

The A₃ adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches

A₃ Adenosine Receptors as Modulators of Inflammation: From Medicinal Chemistry to Therapy

Pharmacophoric Models and 3D QSAR Studies of the Adenosine Receptor Ligands

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Structure–activity relationship studies of a new series of imidazo[2,1-f]purinones as potent and selective A3 adenosine receptor antagonists

Cited by 14 publications

References 44 publications

The A3 adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches

The A3 adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches

A3 Adenosine Receptors as Modulators of Inflammation: From Medicinal Chemistry to Therapy

Pharmacophoric Models and 3D QSAR Studies of the Adenosine Receptor Ligands

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Product

Resources

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The A₃ adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches

The A₃ adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches

A₃ Adenosine Receptors as Modulators of Inflammation: From Medicinal Chemistry to Therapy