To our knowledge BAY has not progressed to clinical developm
To our knowledge, BAY 60-6583 has not progressed to clinical development and remains to be the only ADORA2B agonist that has been developed.33, 34 Further development of similar compounds would be beneficial in future fibrosis research.
One of the limitations of our study is being limited to in vitro findings. Although we have used primary fibroblasts isolated from fresh human tissue, there is always the risk of our findings not being able to be translated to in vivo. Similarly, the IC50 of BAY 60-6583 is relatively high; it is un-likely that such a concentration can be reached at tissue level in an in vivo situation. Further work would be required to understand the pharmacology of ADORA2B agonists in PD. Another limitation is the choice of non-PD TA tissue being obtained from patients with penile cancer. Although we made sure that the tissue obtained was away from the tumor and the tumor margins were negative in histology examination, we cannot exclude the possibility of cancer genetics influencing the fibroblast phenotype.
Conclusion Inhibition of differentiation of quiescent fibroblasts to pro-fibrotic myofibroblasts has been suggested as a therapeutic approach for fibrosis. The effect of BAY 60-6583 on TGF-β1-induced myofibroblast transformation may suggest a novel potential therapeutic target for PD if applied during early, non-stable phase of PD and in other fibro-proliferative diseases, although we did not test the compounds on online derived from the acute phase of PD. We suggest that such compounds may be useful in early stages of the disease to prevent formation of the plaque.
Statement of authorship
Introduction Since adenosine receptor-mediated signaling plays a role in modulating the progression of various pathological disorders, the creation of efficient and safe pharmacological ligands has considerable therapeutic potential, but is fraught with difficulty (Chen et al., 2013). Efforts in medicinal and organic chemistry have been fruitful and numerous adenosine analogues with high affinity and selectivity have been generated (Fredholm et al., 2001, Fredholm et al., 2011). Therefore, the lack of selective ligands is not the major problem. The biggest challenge to overcome is the widespread expression of adenosine receptors and the redundancy of adenosine signaling.
Challenges associated with pharmacological targeting of adenosine signaling
Potential approaches to target adenosine receptor signaling
Conclusions There are many ongoing or already completed phase I-III clinical trials with adenosine receptor ligands for various diseases, but for all the above mentioned reasons few of them may reach the clinic. So far, the clinical applications of adenosine itself, A1AR, A2AAR and A3AR agonists, caffeine, A1AR and A2AAR antagonists have been tested against several pathologies such as liver ischemia and liver cancer, treatment after stenting, blood flow in T1D, wound healing after foot ulcers in T1D and T2D, psoriasis, rheumatoid arthritis, acute heart failure and Parkinson's disease (Avni et al., 2010, Chen et al., 2013, Fernandez et al., 2010, Fishman et al., 2012, Massie et al., 2010, Pinna, 2009, Powers et al., 2008, Schmidt et al., 2006, Schmidt et al., 2007, Silverman et al., 2008). Some of the findings from these clinical trials are promising, but in many cases the tested drugs seem to be ineffective indicating the importance of overcoming the above mentioned obstacles. For example, there are several studies showing that non-selective adenosine receptor inhibitors improve hypoglycemia unawareness in T1D or insulin secretion in T2D (Arias et al., 2001, de Galan et al., 2002). Moreover, pharmacological agents that lead to higher extracellular concentration of adenosine decrease albuminuria in diabetic patients (Aizawa et al., 1990). However, so far there are no data from large-scale clinical trials or from more selective adenosine receptor ligands. In addition, a large-scale trial where adenosine was administrated as an adjunct to reperfusion in the treatment of acute myocardial infarction concluded that adenosine did not prevent the development of heart failure but was able to significantly reduce the infract size (Ross et al., 2005). Parkinson's disease is also another example of pathology where targeting of the adenosine receptors seem to have a therapeutic potential (Lopes et al., 2011). Despite encouraging findings of the administration of A2AAR antagonists in rodent and primate models of Parkinson's disease, these effects have proven difficult to demonstrate on a consistent basis in humans (Morelli et al., 2009). Therefore, the design of more targeted proper clinical studies is a necessity to establish the therapeutic value. According to the current bibliographic literature, and everything mentioned above, more selective targeting of A1AR, A2AAR, A2BAR and A3AR would be a very promising approach provided that issues, such as age of the individuals, main targeted tissue, stage and type of the disease, are carefully taken into consideration.