A2b adenosine receptor antagonists

Vidal and co-workers used 2-oxazolylzinc chloride to enhance an SAR study of orally efficacious A2B adenosine receptor antagonists. The oxazole was also appended through the C4 position by utilizing a Stille reaction of the C4 stannane. ... 

Figure 3.6 Structures of the lead amide 9, and A2B adenosine receptor antagonist, and its bioisosteric analogues 10-13.

As described above, a series of 5-pyridylaminothiazoles had been designed and synthesised as highly potent and selective antagonists at the adenosine A3 receptor (Press et al. 2004). It was essentially an extension of the structure-activity relationship to involve 5-imidazo and 5-triazolo substituted aminothiazoles which enabled the rapid identification of several dual A2B/A3 receptor antagonists with acceptable selectivity over the A and A2a receptors. Of the lead compounds, the mesylate salt of 3-[5-(meth-ylimidazol-l-yl)-2-(pyrazin-2-ylamino)-thiazol-4-yl benzonitrile (QAF805) was considered to be the superior compound (Compound 5f - Press et al. 2005). 

Fig. 2.2 Scatter plot of -TAS° versus AH° values for the adenosine A3 receptor ligands (n = 11) studied obtained in hA3 CHO cells (a). Scatter plot of a typical series of adenosine compounds (n = 85) for the A, A2A, A2B and A3 adenosine receptor subtypes (b). Full and open symbols indicate antagonists and agonists, respectively. All points lie on a same regression line. The two dashed lines indicate the loci of the points representing possible combinations of AH° and -TAS° values giving rise to the two different equilibrium constants indicated (KA = 104 and KA = 1011 M )...

Taken together, using a mouse model of hindlimb skeletal muscle injury, all three adenosine receptor subtypes could each individually induce protection from ischemia-reperfusion injury in skeletal muscle. Due to the lack of a highly selective A2B receptor agonist and antagonist, its role in mediating an anti-ischemic effect in skeletal muscle remains to be determined. 

Adenosine binds to adenosine receptors (AD-Rs) (subtypes Ah A2A, A2b and A3). Ap and Ap R activation gives Gai-mediated inhibition of adenylyl cyclase (resulting in decreased cAMP) and Gai/Gao-mediated activation of a K+ channel (with a de-excitatory hyperpolarizing effect). A2A and A2B activation gives Gas-mediated stimulation of adenylate cyclase (resulting in elevated cAMP). Adenosine acting via particular receptors variously has cardioprotective, neuroprotective, sedative, anticonvulsant, soporific, vasodilatory and bronchoconstrictive effects. The plant-derived methylxanthines theophylline and caffeine are adenosine A1 and A2 receptor antagonists (Table 5.1). 

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