Discovery and Characterization of 4‘-(2-Furyl)-<i>N</i>-pyridin-3-yl-4,5‘-bipyrimidin-2‘-amine (LAS38096), a Potent, Selective, and Efficacious A<sub>2B</sub> Adenosine Receptor Antagonist

Vidal, Bernat; Nueda, Arsenio; Esteve, Cristina; Domènech, Teresa; Benito, Sonia; Reinoso, Raquel F.; Pont, Mercè; Calbet, Marta; López, Rosa; Cadavid, Marı́a Isabel; Loza, Marı́a Isabel; Cárdenas, A. de Pablo; Godessart, Núria; Beleta, Jörge; Warrellow, Graham J.; Ryder, Hamish

doi:10.1021/jm061333v

Cited by 32 publications

(34 citation statements)

References 26 publications

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“…More data are available in the Almirall patent applications or in subsequent publications for bipyrimidine [65][66], imidazopyridine [67], and pyrazine [68] based antagonists ( Table 9). …”

Section: Non-xanthinementioning

confidence: 99%

“…The lead compound of this series is LAS-38096 (42) [65][66], whose good profile of affinity and selectivity was maintained in all the derivatives. LAS-38096 displayed a favorable pharmacokinetic profile in preclinical species and showed efficacy in functional in vitro and in vivo models of allergy and inflammation; therefore, it was moved on preclinical in vivo safety and toxicology studies.…”

Section: Non-xanthinementioning

confidence: 99%

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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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“…More data are available in the Almirall patent applications or in subsequent publications for bipyrimidine [65][66], imidazopyridine [67], and pyrazine [68] based antagonists ( Table 9). …”

Section: Non-xanthinementioning

confidence: 99%

Section: Non-xanthinementioning

confidence: 99%

A2B Receptor Ligands: Past, Present and Future Trends

Ortore¹,

Martinelli²

2010

CTMC

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“…The molecular docking performed for the 4 0 -furan-2-yl-N-pyridin-3-yl-4,5 0 -bipyrimidin-2 0 -amines as potent and selective adenosine A 2B receptor antagonist [55] (compounds 15, 16, and 17 in Fig. 2) suggests that Asn254 is involved in an interaction with the furan oxygen atom and the amino group at the 2 0 -position of the ligand and the furan moiety of the ligand is located in the pocket formed by Thr89, His251, Val191, and Leu86.…”

Section: Phe173mentioning

confidence: 99%

Homology modelling of the human adenosine A2B receptor based on X-ray structures of bovine rhodopsin, the β2-adrenergic receptor and the human adenosine A2A receptor

Sherbiny

Schiedel²,

Maaß

et al. 2009

J Comput Aided Mol Des

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A three-dimensional model of the human adenosine A2B receptor was generated by means of homology modelling, using the crystal structures of bovine rhodopsin, the beta2-adrenergic receptor, and the human adenosine A2A receptor as templates. In order to compare the three resulting models, the binding modes of the adenosine A2B receptor antagonists theophylline, ZM241385, MRS1706, and PSB601 were investigated. The A2A-based model was much better able to stabilize the ligands in the binding site than the other models reflecting the high degree of similarity between A2A and A2B receptors: while the A2B receptor shares about 21% of the residues with rhodopsin, and 31% with the beta2-adrenergic receptor, it is 56% identical to the adenosine A2A receptor. The A2A-based model was used for further studies. The model included the transmembrane domains, the extracellular and the intracellular hydrophilic loops as well as the terminal domains. In order to validate the usefulness of this model, a docking analysis of several selective and nonselective agonists and antagonists was carried out including a study of binding affinities and selectivities of these ligands with respect to the adenosine A2A and A2B receptors. A common binding site is proposed for antagonists and agonists based on homology modelling combined with site-directed mutagenesis and a comparison between experimental and calculated affinity data. The new, validated A2B receptor model may serve as a basis for developing more potent and selective drugs.

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“…Pyrimidine cores belong to one of the most important heterocycles and as such make attractive scaffolds in medicinal chemistry. Pyrimidine derivatives have diverse biological activities [4–11] and are found in many medicines as well as genetic materials including nucleosides and nucleotides. Pyrimidines are also reported to occur in some pesticides, herbicides, and plant growth regulators [12, 13].…”

Section: Introductionmentioning

confidence: 99%

Microwave‐assisted one‐pot synthesis of functionalized pyrimidines using ionic liquid

Raghuvanshi

Singh

2011

Journal of Heterocyclic Chem

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An efficient one‐pot multicomponent synthesis of 2,4‐diamino‐5‐pyrimidinecarbonitrile derivatives has been achieved in excellent yields by the condensation of aromatic aldehydes, malononitrile, and guanidine using ionic liquid under controlled microwave irradiation (100 W) at 60°C. This green approach offers a number of advantages in terms of methodology, high‐product yield, short reaction time, mild reaction conditions, and easy workup. J. Heterocyclic Chem., (2011).

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Discovery and Characterization of 4‘-(2-Furyl)-N-pyridin-3-yl-4,5‘-bipyrimidin-2‘-amine (LAS38096), a Potent, Selective, and Efficacious A_2B Adenosine Receptor Antagonist

Cited by 32 publications

References 26 publications

A2B Receptor Ligands: Past, Present and Future Trends

A2B Receptor Ligands: Past, Present and Future Trends

Homology modelling of the human adenosine A2B receptor based on X-ray structures of bovine rhodopsin, the β2-adrenergic receptor and the human adenosine A2A receptor

Microwave‐assisted one‐pot synthesis of functionalized pyrimidines using ionic liquid

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Discovery and Characterization of 4‘-(2-Furyl)-N-pyridin-3-yl-4,5‘-bipyrimidin-2‘-amine (LAS38096), a Potent, Selective, and Efficacious A2B Adenosine Receptor Antagonist

Cited by 32 publications

References 26 publications

A2B Receptor Ligands: Past, Present and Future Trends

A2B Receptor Ligands: Past, Present and Future Trends

Homology modelling of the human adenosine A2B receptor based on X-ray structures of bovine rhodopsin, the β2-adrenergic receptor and the human adenosine A2A receptor

Microwave‐assisted one‐pot synthesis of functionalized pyrimidines using ionic liquid

Contact Info

Product

Resources

About

Discovery and Characterization of 4‘-(2-Furyl)-N-pyridin-3-yl-4,5‘-bipyrimidin-2‘-amine (LAS38096), a Potent, Selective, and Efficacious A_2B Adenosine Receptor Antagonist