Synthesis and pharmacological evaluation of novel 1- and 8-substituted-3-furfuryl xanthines as adenosine receptor antagonists

Balo, María Carmen; Brea, José; Caamaño, Olga; Fernández, Fernando Nieto; Garcı́a-Mera, Xerardo; López, Carmen; Loza, Marı́a Isabel; Nieto, Marı́a Luisa; Rodríguez‐Borges, José E.

doi:10.1016/j.bmc.2009.07.034

Cited by 11 publications

(5 citation statements)

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“…One of the last and original variations regarded the insertion of a 3-methoxy propyl substituent [45] or a furfuryl [46] at 3-position of the xanthine core, correlated to various modifications at the 1-and 8-positions. Some of the 1-ethyl-3-(3-methoxy propyl)-8-aryl xanthines showed moderate-tohigh affinity at human A 2B AR, in particular compound 28 showed A 2B selectivity over the other adenosine subtypes of 34-fold or over.…”

Section: Xantinementioning

confidence: 99%

A2B Receptor Ligands: Past, Present and Future Trends

Ortore¹,

Martinelli²

2010

CTMC

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A(2B) adenosine receptors have been investigated in recent years as potential target for the treatment of different pathologies. The involvement of this receptor in processes such as interleukins secretion, Ca(2+) mobilization, hepatic glucose regulation, tumor vascularisation, and cardioprotection have stimulated many researchers to develop specific agonists and antagonists. For many years, the lack of potent and selective A(2B) ligands precluded a deep exploration of their therapeutic prospective; at present, much progress in the field of antagonists led to preclinical studies for different compounds. Less populated is the universe of A(2B) agonists, but really promising for the involvement in ischemic preconditioning. A summary of the most significant advancements in the synthesis of new compounds and of the principal structure activity relationships is reported. The xanthine-based A(2B) antagonists currently show the better profile of affinity and selectivity, as CVT-6883 (CVT-Therapeutics: K(i(A2B))=22 nM, and selectivity higher than 50-fold over other subtypes), MRE-2029-F20 (Baraldi's group: K(i(A2B))=5.5 nM, selectivity >180 fold), LAS38096 (Almirall Prodesfarma: K(i(A2B))=17 nM, selectivity >60 fold), OSIP339391 (OSI Pharmaceuticals: K(i(A2B))=0.5 nM, selectivity >80 fold), PSB601 (Bonn University: K(i(A2B))=3.6 nM, selectivity >140 fold) and the deazaxanthine 32 of Carotti's group (K(i(A2B))=11 nM, selectivity >90 fold). Other recently emerging scaffolds with promising biological profiles are described. With regard to the agonists, many research groups are involved in the discovery of useful agonist radioligands, but the only example of potent and rather selective A(2B) agonists are compound 65, recently synthesized, and BAY-60-6583, that is under preclinical phase investigation.

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Section: Xantinementioning

confidence: 99%

A2B Receptor Ligands: Past, Present and Future Trends

Ortore¹,

Martinelli²

2010

CTMC

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“…2 and table 2). Some of them showed high A 2B affinity but only moderate selectivity (Balo et al 2009). …”

Section: Adenosine A2b Receptor Antagonistsmentioning

confidence: 99%

Xanthines as Adenosine Receptor Antagonists

Müller

Jacobson

2010

Handbook of Experimental Pharmacology

115

109

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The natural plant alkaloids caffeine and theophylline were the first adenosine receptor (AR) antagonists described in the literature. They exhibit micromolar affinities and are non-selective. A large number of derivatives and analogs have subsequently been synthesized and evaluated as AR antagonists. Very potent antagonists have thus been developed with selectivity for each of the four AR subtypes.

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“…From a structural point of view, A 2B AR antagonists can be subdivided into two classes, namely, xanthines and nonxanthine heterocyclic derivatives (Figure ). − The discovery of the (nonselective) micromolar antagonistic profile of the natural alkaloids caffeine and theophylline motivated the synthesis of thousands of xanthine congeners . The systematic modification at positions 1, 3, and 8 of the xanthine scaffold enabled the development of potent and selective A 2B AR ligands (Figure , compounds 2 – 5 ). − Similarly, pharmacomodulation of the heterobicyclic core at the physiological agonist (adenosine) provided adenine derivatives that exhibit attractive A 2B AR profiles.…”

Section: Introductionmentioning

confidence: 99%

“… − The discovery of the (nonselective) micromolar antagonistic profile of the natural alkaloids caffeine and theophylline motivated the synthesis of thousands of xanthine congeners . The systematic modification at positions 1, 3, and 8 of the xanthine scaffold enabled the development of potent and selective A 2B AR ligands (Figure , compounds 2 – 5 ). − Similarly, pharmacomodulation of the heterobicyclic core at the physiological agonist (adenosine) provided adenine derivatives that exhibit attractive A 2B AR profiles. However, while these derivatives provided valuable compounds that enabled an exhaustive exploration of the structure, signaling, and (patho)physiological roles of A 2B AR, a major drawback of xanthine derivatives and adenine-related AR ligands is their generally low water solubility.…”

Section: Introductionmentioning

confidence: 99%

“…Resembling the ribose moiety of the endogen ligand (adenosine), pentagonal heterocyclic cores (e.g., furan and thiophene rings) are common motifs in the structures of AR antagonists (Figure ). ,− The electron-rich nature of the heterocyclic core means that some of these scaffolds can be classified as putative structural alerts . Hence, the early identification of structural elements that have the potential to become structural alerts constitutes a key issue during early drug discovery.…”

Section: Introductionmentioning

confidence: 99%

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Nitrogen-Walk Approach to Explore Bioisosteric Replacements in a Series of Potent A_2B Adenosine Receptor Antagonists

Mallo-Abreu¹,

Prieto-Díaz²,

Jespers

et al. 2020

J. Med. Chem.

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A systematic exploration of bioisosteric replacements for furan and thiophene cores in a series of potent A 2B AR antagonists has been carried out using the nitrogen-walk approach. A collection of 42 novel alkyl 4-substituted-2-methyl-1,4dihydrobenzo [4,5]imidazo[1,2-a]pyrimidine-3-carboxylates, which contain 18 different pentagonal heterocyclic frameworks at position 4, was synthesized and evaluated. This study enabled the identification of new ligands that combine remarkable affinity (K i < 30 nM) and exquisite selectivity. The structure−activity relationship (SAR) trends identified were substantiated by a molecular modeling study, based on a receptor-driven docking model and including a systematic free energy perturbation (FEP) study. Preliminary evaluation of the CYP3A4 and CYP2D6 inhibitory activity in optimized ligands evidenced weak and negligible activity, respectively. The stereospecific interaction between hA 2B AR and the eutomer of the most attractive novel antagonist (S)-18g (K i = 3.66 nM) was validated.

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Synthesis and pharmacological evaluation of novel 1- and 8-substituted-3-furfuryl xanthines as adenosine receptor antagonists

Cited by 11 publications

References 24 publications

A2B Receptor Ligands: Past, Present and Future Trends

A2B Receptor Ligands: Past, Present and Future Trends

Xanthines as Adenosine Receptor Antagonists

Nitrogen-Walk Approach to Explore Bioisosteric Replacements in a Series of Potent A_2B Adenosine Receptor Antagonists

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Synthesis and pharmacological evaluation of novel 1- and 8-substituted-3-furfuryl xanthines as adenosine receptor antagonists

Cited by 11 publications

References 24 publications

A2B Receptor Ligands: Past, Present and Future Trends

A2B Receptor Ligands: Past, Present and Future Trends

Xanthines as Adenosine Receptor Antagonists

Nitrogen-Walk Approach to Explore Bioisosteric Replacements in a Series of Potent A2B Adenosine Receptor Antagonists

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Product

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Nitrogen-Walk Approach to Explore Bioisosteric Replacements in a Series of Potent A_2B Adenosine Receptor Antagonists