N6-[(Hetero)aryl/(cyclo)alkyl-carbamoyl-methoxy-phenyl]-(2-chloro)-5′-N-ethylcarboxamido-adenosines: The first example of adenosine-related structures with potent agonist activity at the human A2B adenosine receptor

Baraldi, Pier Giovanni; Preti, Delia; Tabrizi, Mojgan Aghazadeh; Fruttarolo, Francesca; Saponaro, Giulia; Baraldi, Stefania; Romagnoli, Romeo; Moorman, Allan R.; Gessi, Stefania; Varani, Katia; Borea, Pier Andrea

doi:10.1016/j.bmc.2007.01.055

Cited by 65 publications

(74 citation statements)

References 31 publications

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“…7,[22][23] Furthermore, hypoxia stabilizes HIFs and leads to the accumulation of ado. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] This study reports, for the first time, that ado increases HIF-1␣ protein levels in U937, HMs, and FCs in hypoxia as already observed in cancer cells. 19,[25][26] A 2B and A 3 subtypes play a major role in the VEGF increase and FC formation and only the A 2B is responsible for IL-8 stimulation induced by adenosine.…”

Section: Discussionmentioning

confidence: 81%

“…As shown in Figure 2A the ado effect was partially antagonized by 100 nmol/L DPCPX, SCH 58261, MRE 2029F20, and MRE 3008F20 suggesting the involvement of A 1 , A 2A , A 2B , and A 3 ARs, respectively. Therefore we evaluated the effect of high affinity agonists, CHA, CGS 21680, Compound 24, 21 and Cl-IB-MECA on HIF-1␣ accumulation. Probes selectivity is provided in supplemental Table II.…”

Section: Involvement Of Ars In Ado-induced Hif-1␣ Expressionmentioning

confidence: 99%

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Adenosine Modulates HIF-1α, VEGF, IL-8, and Foam Cell Formation in a Human Model of Hypoxic Foam Cells

Gessi

Fogli

Sacchetto

et al. 2010

ATVB

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Objective-Foam cell (FC) formation by oxidized low-density lipoprotein (oxLDL) accumulation in macrophages is crucial for development of atherosclerosis. Hypoxia has been demonstrated in atherosclerosis and hypoxia-inducible factor-1 (HIF-1) has been shown to promote intraplaque angiogenesis and FC development. M acrophage foam cell formation is an important process in atherosclerotic plaque development. 1 Atherosclerosis is initiated by dysfunction of endothelial cells at lesionprone sites in the walls of arteries, which results in monocyte infiltration into the arterial intima. These cells differentiated into macrophages, which then internalize large amounts of oxidized low-density lipoprotein forming cholesterol-laden macrophages called "foam cells" (FCs), which in turn give rise to fatty streaks in the arterial wall. 2 As the atherosclerotic lesion develops, the arterial wall thickness increases and oxygen diffusion into the intima is markedly reduced. These hypoxic regions contain large number of FCs revealing that these cells experience hypoxia during the development of atherosclerotic lesions. 3-4 Hypoxia-inducible factor-1 (HIF-1), the most important factor involved in the cellular response to hypoxia, is a heterodimeric transcription factor composed of an inducibly expressed HIF-1␣ subunit and a constitutively-expressed HIF-1␤ subunit. 5 It is well established that HIF plays a major role in vascular endothelial growth factor (VEGF) expression and angiogenesis, mediating important alterations associated with atherogenesis and angiogenic activity of macrophages. 6 -7 Moreover, under atherogenic conditions, the high expression of HIF-1 in macrophages promotes FC formation and atherosclerosis. 8

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Section: Discussionmentioning

confidence: 81%

Section: Involvement Of Ars In Ado-induced Hif-1␣ Expressionmentioning

confidence: 99%

Adenosine Modulates HIF-1α, VEGF, IL-8, and Foam Cell Formation in a Human Model of Hypoxic Foam Cells

Gessi

Fogli

Sacchetto

et al. 2010

ATVB

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“…39) The reaction of commercially available 2,5-dimercapto-1,3,4-thiadiazole with compound 4 in the presence of NaOH in water and ethanol at room temperature yielded the desired intermediates 5a-k in 70-81% yields. Finally, the target compounds 6a-k, 7a-k and 8a-k were successfully obtained by the reaction of intermediates 5a-k and compound 2 in the presence of NaHCO 3 in methanol and water at room temperature.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis and Antiproliferative Evaluation of Novel Disulfides Containing 1,3,4-Thiadiazole Moiety

Zhang

Liu

Tang

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…1) displaying submicromolar potency in activating the A 2B AR subtype [64]. -(hetero)aryl-carbamoyl-methoxy-phenyl)-(2-chloro)-NECA derivatives 7-18 at the human adenosine receptors expressed in CHO cells [69] groups yielded compounds endowed with similar activity as the corresponding adenosine analogues (N 6 -(4-chlorophenyl) NECA, 5, EC 50 =0.73 μM) [67]. In a recent study of modelling and site-directed mutagenesis performed with the aim of defining the leading parameters affecting the interaction between A 2A AR and its specific agonists [68], the N 6 -guanidino derivative 6 of NECA ( Fig.…”

Section: Adenosine-like Ligandsmentioning

confidence: 99%

Recent improvements in the development of A2B adenosine receptor agonists

Baraldi

Tabrizi²,

Fruttarolo³

et al. 2009

Purinergic Signalling

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Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named A 1 , A 2A , A 2B and A 3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A 2B AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A 2B AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview of the recent advancements in identifying potent and selective A 2B AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine ligands. Nucleosidebased agonists are the result of modifying adenosine by substitution at the N 6 -, C 2 -positions of the purine heterocycle and/or at the 5′-position of the ribose moiety or combinations of these substitutions. Compounds 1-deoxy-and its 2-chloro analogue 23 (hA 1 K i =3500 nM, hA 2A K i = 4950 nM, hA 2B EC 50 =210 nM, hA 3 K i >5 μM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay in Chinese hamster ovary (CHO) cells expressing hA 2B AR.Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3, 5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY-60-6583, hA 1 , hA 2A , hA 3 EC 50 >10 μM; hA 2B EC 50 =3 nM) is currently under preclinicalphase investigation for treating coronary artery disorders and atherosclerosis.

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N6-[(Hetero)aryl/(cyclo)alkyl-carbamoyl-methoxy-phenyl]-(2-chloro)-5′-N-ethylcarboxamido-adenosines: The first example of adenosine-related structures with potent agonist activity at the human A2B adenosine receptor

Cited by 65 publications

References 31 publications

Adenosine Modulates HIF-1α, VEGF, IL-8, and Foam Cell Formation in a Human Model of Hypoxic Foam Cells

Adenosine Modulates HIF-1α, VEGF, IL-8, and Foam Cell Formation in a Human Model of Hypoxic Foam Cells

Design, Synthesis and Antiproliferative Evaluation of Novel Disulfides Containing 1,3,4-Thiadiazole Moiety

Recent improvements in the development of A2B adenosine receptor agonists

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