Discovery of potent and selective bicyclic A2B adenosine receptor antagonists via bioisosteric amide replacement

Eastwood, Paul; González, Jacob; Paredes, Sergio; Fonquerna, Sı́lvia; Cardús, Arantxa; Alonso, Juan Antonio; Nueda, Arsenio; Domènech, Teresa; Reinoso, Raquel F.; Vidal, Bernat

doi:10.1016/j.bmcl.2010.01.077

Cited by 18 publications

(21 citation statements)

References 23 publications

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“…71 ) [174], pyridine derivatives (e.g. 72 , 73 ) [171,175], have been developed as A 2B antagonists. Compound 72 was shown to be metabolically unstable.…”

Section: Adenosine Receptor Antagonistsmentioning

confidence: 99%

Recent developments in adenosine receptor ligands and their potential as novel drugs

Müller

Jacobson

2011

Biochimica et Biophysica Acta (BBA) - Biomembranes

393

461

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Medicinal chemical approaches have been applied to all four of the adenosine receptor (AR) subtypes (A1, A2A, A2B, and A3) to create selective agonists and antagonists for each. The most recent class of selective AR ligands to be reported is the class of A2BAR agonists. The availability of these selective ligands has facilitated research on therapeutic applications of modulating the ARs and in some cases has provided clinical candidates. Prodrug approaches have been developed which improve the bioavailability of the drugs, reduce side-effects, and/or may lead to site-selective effects. The A2A agonist regadenoson (Lexiscan®), a diagnostic drug for myocardial perfusion imaging, is the first selective AR agonist to be approved. Other selective agonists and antagonists are or were undergoing clinical trials for a broad range of indications, including capadenoson and tecadenoson (A1 agonists) for atrial fibrillation, or paroxysmal supraventricular tachycardia, respectively, apadenoson and binodenoson (A2A agonists) for myocardial perfusion imaging, preladenant (A2A antagonist) for the treatment of Parkinson’s disease, and CF101 and CF102 (A3 agonists) for inflammatory diseases and cancer, respectively. This article is part of a Special Issue entitled: “Adenosine Receptors”.

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“…71 ) [174], pyridine derivatives (e.g. 72 , 73 ) [171,175], have been developed as A 2B antagonists. Compound 72 was shown to be metabolically unstable.…”

Section: Adenosine Receptor Antagonistsmentioning

confidence: 99%

Recent developments in adenosine receptor ligands and their potential as novel drugs

Müller

Jacobson

2011

Biochimica et Biophysica Acta (BBA) - Biomembranes

393

461

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“…In contrast, the A 2B AR subtype is the least known. In fact, while a large number of selective A 2B AR antagonists belonging to different chemical classes has been developed [4][5][6][7][8][9][10], only a few A 2B AR agonists are known so far [11]. As antagonists are characterized by a large structural variability, the agonist profile has been long associated to an Ado-like structure.…”

Section: Introductionmentioning

confidence: 99%

The aminopyridine-3,5-dicarbonitrile core for the design of new non-nucleoside-like agonists of the human adenosine A2B receptor

Betti

Catarzi

Varano

et al. 2018

European Journal of Medicinal Chemistry

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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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“…Other frequently used ring closure ideas include converting an alkyl chain to cyclohexane, piperizine or piperidine [51], converting an o -hydroxylbenzoyl group to quinazoline [52], and converting an arylamine or arylamide to a fused ring system [53]. …”

Section: Classification Of Scaffold Hopping Approachesmentioning

confidence: 99%

Classification of scaffold-hopping approaches

Sun

Tawa

Wallqvist

2012

Drug Discovery Today

301

258

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The general goal of drug discovery is to identify novel compounds that are active against a preselected biological target with acceptable pharmacological properties defined by marketed drugs. Scaffold hopping has been widely applied by medicinal chemists to discover equipotent compounds with novel backbones that have improved properties. In this review, scaffold hopping is classified into four major categories, namely heterocycle replacements, ring opening or closure, peptidomimetics, and topology-based hopping. The structural diversity of original and final scaffolds with respect to each category will be reviewed. The advantages and limitations of small, medium, and large-step scaffold hopping will also be discussed. Software that is frequently used to facilitate different kinds of scaffold hopping methods will be summarized.

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Discovery of potent and selective bicyclic A2B adenosine receptor antagonists via bioisosteric amide replacement

Cited by 18 publications

References 23 publications

Recent developments in adenosine receptor ligands and their potential as novel drugs

Recent developments in adenosine receptor ligands and their potential as novel drugs

The aminopyridine-3,5-dicarbonitrile core for the design of new non-nucleoside-like agonists of the human adenosine A2B receptor

Classification of scaffold-hopping approaches

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