Recent improvements in the development of A2B adenosine receptor agonists

Baraldi, Pier Giovanni; Tabrizi, Mojgan Aghazadeh; Fruttarolo, Francesca; Romagnoli, Romeo; Preti, Delia

doi:10.1007/s11302-009-9140-8

Cited by 34 publications

(25 citation statements)

References 86 publications

(65 reference statements)

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“…The SAR of adenosine agonists at the A 2B AR was recently reviewed [11,13]. Substitution of adenosine at the N 6 -position with a narrow range of aryl groups increases affinity at the A 2B AR.…”

Section: Adenosine Receptor Agonistsmentioning

confidence: 99%

“…3). Thus, combinations of narrowly defined modifications have resulted in compounds that interact selectively with A 2B AR [11,46] or that activate the A 2B AR along with the A 2A AR (MRS3997, 27 ) [47]. …”

Section: Adenosine Receptor Agonistsmentioning

confidence: 99%

“…1–9 and Tables 1–3). The most recent class of selective AR ligands to be reported is the class of A 2B AR agonists [11–13]. The availability of these selective ligands has facilitated research on therapeutic applications of modulating the ARs and in some cases has provided clinical candidates.…”

Section: Introductionmentioning

confidence: 99%

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

Müller

Jacobson

2011

Biochimica et Biophysica Acta (BBA) - Biomembranes

397

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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Section: Adenosine Receptor Agonistsmentioning

confidence: 99%

Section: Adenosine Receptor Agonistsmentioning

confidence: 99%

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

Müller

Jacobson

2011

Biochimica et Biophysica Acta (BBA) - Biomembranes

397

461

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“…Furthermore, also the evaluation of this receptor as pharmacological target, and then of its therapeutic application, was hampered by the lack of agonist radioligands. Compounds with a detectable activity on A 2B AR were reported in recent literature [28,29], and can be classified into adenosine-like and non-adenosine-like ligands.…”

Section: A 2b Adenosine Receptor Agonistsmentioning

confidence: 99%

“…But in the last years, several ligands able to activate A 2B AR have been identified [28,29], and a phenyl pyridinesulfenyl acetamide derivative is currently under preclinical investigation in the treatment of atherosclerosis and coronary artery disorders.…”

Section: Introductionmentioning

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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2‐Amino[1,2,4]triazolo[1,5‐c]quinazolines and Derived Novel Heterocycles: Syntheses and Structure–Activity Relationships of Potent Adenosine Receptor Antagonists

et al. 2016

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2-Amino[1,2,4]triazolo[1,5-c]quinazolines were identified as potent adenosine receptor (AR) antagonists. Synthetic strategies were devised to gain access to a broad range of derivatives including novel polyheterocyclic compounds. Potent and selective A AR antagonists were discovered, including 3,5-diphenyl[1,2,4]triazolo[4,3-c]quinazoline (17, K human A AR 1.16 nm) and 5'-phenyl-1,2-dihydro-3'H-spiro[indole-3,2'-[1,2,4]triazolo[1,5-c]quinazolin]-2-one (20, K human A AR 6.94 nm). In addition, multitarget antagonists were obtained, such as the dual A /A antagonist 2,5-diphenyl[1,2,4]triazolo[1,5-c]quinazoline (13 b, K human A AR 51.6 nm, human A AR 11.1 nm), and the balanced pan-AR antagonists 5-(2-thienyl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11 c, K human A AR 131 nm, A AR 32.7 nm, A AR 150 nm, A AR 47.5 nm) and 9-bromo-5-phenyl[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11 q, K human A AR 67.7 nm, A AR 13.6 nm, A AR 75.0 nm, A AR 703 nm). In many cases, significantly different affinities for human and rat receptors were observed, which emphasizes the need for caution in extrapolating conclusions between different species.

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Recent improvements in the development of A2B adenosine receptor agonists

Cited by 34 publications

References 86 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

A2B Receptor Ligands: Past, Present and Future Trends

2‐Amino[1,2,4]triazolo[1,5‐c]quinazolines and Derived Novel Heterocycles: Syntheses and Structure–Activity Relationships of Potent Adenosine Receptor Antagonists

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