Project: cAMP Enhancing approaches for treating pulmonary hypertension

Pulmonary hypertension (PH) is a progressive disease of multifactorial etiology, which has a poor prognosis and results in right heart failure. In all it's variant forms, it is estimated to affect up to 100 million people worldwide. Among these, pulmonary arterial hypertension (PAH), a fatal form of PH, is characterized by structural narrowing of small pulmonary arteries. Although the pathogenesis of PAH is multifactorial, it is thought to arise, in part, from disturbances in the balance between endogenous vasoconstrictors, such as endothelin, and vasodilators, such as prostacyclin and nitric oxide, in response to endothelial dysfunction/injury (Galie` N et al 2004). These discoveries have led to the development of therapies targeted at the prostacyclin-, nitric oxide- and endothelin mediated pathways, with treatments designed to promote vasodilation and inhibit cell growth. Currently approved agents fall into one of three pharmacological classes: prostacyclin analogues, endothelin receptor antagonists (ETRA) and PDE5 inhibitors. _x000D__x000D_Because of the propensity of PAH to affect younger individuals and its associated high morbidity and mortality, its impact on quality-adjusted life years is substantial. The costs of medical therapy are ranging from $20,000 to well over $250,000 a year. The persistent high morbidity and mortality in PAH, despite the currently available treatments, highlight the need for novel therapeutic pathways. _x000D__x000D_One of the strategies for developing new PAH treatment candidates is targeting downstream components of the NO and prostacyclin signalling pathway is by preventing the degradation of cGMP and cAMP. It has been shown that cAMP and cGMP phosphodiesterase (PDE) activity is increased and an upregulation of selective PDE isoforms was observed in animal models of PAH (MacLean et al, 1997; Pullamsetti et al, 2011) as well as in patients with PAH (Murray et al, 2007). On the basis of this rationale, some inhibitors of PDE5 have been developed and approved as PAH therapies. Since at least 11 members of the PDE family (Soderling & Beavo, 2000) have been described, a vast field related to PAH pathobiology and PDEs pharmacology reCO to be explored. For example, PDE3 inhibitors have been shown beneficial in reducing pulmonary vasoconstriction in experimental models of PAH (Murray F, 2002). Recently, it has been also demonstrated a central role of PDE10A in progressive pulmonary vascular remodelling, and suggested PDE10A inhibitors as novel therapeutic approach for the treatment of PAH (Tian et al, 2011). _x000D__x000D_On the other hand, adenosine signalling that also mediates the regulation of cAMP levels has been implicated as well in pulmonary vasoconstriction, which in turn may causes PH. The contractile response caused by hypoxia is mediated via A1 receptors and abolished by adenosine A1 receptor (Aa1R) antagonist (Broadley et al, 1996). An alternative possibility for development rational therapies for PAH can be targeting the adenosine signalling. Regarding to this, Palobiofarma S.L has developed and patented an adenosine A1 receptor antagonist (PBF-680) that has reached successfully the IND status and it is ready for starting the clinical trials in the second quarter of 2013._x000D__x000D_Finally, due to the complexity of the mechanisms that trigger PAH, other emerging therapeutic approach is the use of drug combinations for targeting multiple pathways in order to achieve synergistic therapeutic responses. Sequential addition of agents from different classes in patients not responding optimally to single or dual agent therapies is in widespread use in PH clinical practice. _x000D__x000D_On the basis of the above explained, the present project aims to accomplish four specific objectives:_x000D__x000D_1) Assess the safety and tolerability of an adenosine A1 receptor antagonist (PBF-680) in healthy volunteers (Phase I clinical trial)._x000D__x000D_2) Efficacy studies of several adenosine receptors and PDE inhibitors through different animal models of PAH. _x000D__x000D_3) Discovery of a new class of dual PDE10/A1 inhibitors as novel candidates for PAH treatment._x000D__x000D_4) Study of the combination of the different developed compounds (A1 receptor antagonists and PDE inhibitors) in different in vitro and in vivo models of PAH._x000D__x000D_To achieve these goals the company Palobiofarma S.L, a spanish drug discovery company focused in adenosine receptor modulators and Max Planck Institute for Heart and Lung Research (part of Max Planck Society), a German academic institution specialized in PH, have joined their capacities and their complementary expertise. The roles of each institution in the project are as follows_x000D__x000D_a) Palobiofarma will be focused on the discovery of new dual PDE10/A1 Inhibitors, as well as in conducting a safety and tolerability study of the PBF-680 in humans._x000D__x000D_b) Max Planck Institute will be involved in testing the potency and efficacy of the novel compounds and their combinations (PDE 10 and A1 antagonists) in different in vitro and in vivo models of PAH._x000D_

Acronym PulmocAMP (Reference Number: 8410)
Duration 03/06/2013 - 30/06/2016
Project Topic Novel adenosine A1 receptor and PDE-10 inhibitors as cyclic adenosine monophosphate enhancing compounds as a new generation treatments for pulmonary arterial hypertension
Network Eurostars
Call Eurostars Cut-Off 10

Project partner

Number Name Role Country
2 Palobiofarma S.L Coordinator Spain
2 Max Planck Society Partner Germany