br Conclusions and perspectives In view of

Conclusions and perspectives In view of the evidences supporting that Radotinib MAS receptors mediate the effects of AT1 antagonists (Iwai et al., 2012, Ohshima et al., 2014, Pernomian et al., 2015, Schuchard et al., 2015), the prime targets from the perspectives on future directions in the interplay between angiotensin AT1 and MAS receptors may be the following: (1) the investigation of the role played by MAS receptors on the effects from other AT1 antagonists than those used in the referred studies (olmesartan, azilsartan, candesartan or telmisartan) by comparing the combined blockage of AT1 and MAS receptors with the isolated blockage of AT1 receptors; (2) the design of novel MAS agonists with antagonist properties on AT1 receptors; and (3) the performance of experimental and clinical studies aimed in comparing the pharmacological and therapeutic efficacy of such novel MAS agonists and the available AT1 antagonists. The only currently available nonpeptide and orally active MAS agonist is AVE0991 (Paulis et al., 2015), which was developed by Aventis Pharma Deutschland GmbH (Germany) as an analog of angiotensin-(1-7) (Wiemer et al., 2002) and latter characterized as a MAS agonist but not as an AT1 antagonist (Pinheiro et al., 2004). A few recent experimental studies have shown that AVE0991 elicits in vivo antihypertensive, vasoprotective, cardioprotective, atheroprotective, renoprotective and antiinflammatory effects, suggesting that the nonpeptide MAS agonist would be indicated to treat the cardiovascular and renal damages triggered by hypertension, atherosclerosis, heart and renal failure in future clinical trials (Benter et al., 2006, Ferreira et al., 2007, Toton-Zuranska et al., 2010, Barroso et al., 2012). Such perspectives rely on the conclusion of preclinical toxicological studies, which may be carried out as soon as more evidences regarding the therapeutic efficacy of AVE0991 in the referred clinical conditions were taken from in vivo experimental studies. An interesting challenge on the development of MAS agonizts is the design of novel drugs provided with agonist activity on MAS receptors and antagonist properties on AT1 receptors. In comparative studies, it is feasible to expect that such novel MAS agonizts could overcome the efficacy of the available AT1 antagonists due to a dual positive modulation on the functionality of angiotensin-converting enzyme 2–angiotensin-(1-7)–MAS axis: (1) the direct MAS activation by interacting with MAS receptors or AT1/MAS heterodimers (in the last case enhancing the constitutive AT1 antagonism played by MAS receptors, according to the evidences provided by Kostenis et al. (2005) and Canals et al. (2006)) and (2) the direct antagonism on AT1 receptors.