Adams, J

Behan, D

Clapp, LH

Norel, X

Patel, J

Shen, L

UCL Discovery

APD811 (ralinepag), a novel non-prostanoid IP receptor agonist, has potent antiproliferative and vasorelaxant properties in human pulmonary artery.   Shen L1, Patel J1, Norel X2, Adams J3, Behan D3, Clapp LH1  1Institute of Cardiovascular Science, UCL, London UK 2INSERM U1148, CHU X. Bichat, Paris, France 3Arena Pharmaceuticals, Inc. San Diego, CA USA  Introduction: APD811 is an oral, non-prostanoid IP receptor agonist with a long plasma half-life (∼ 24 hr) in development for pulmonary arterial hypertension (PAH). Little is known about the pulmonary pharmacology of this agent. The aim was to compare the functional effects of APD811 in distal human pulmonary smooth muscle cells (PASMCs) and arteries (PAs) alongside other prostacyclin mimetics already licensed for PAH. Methods: PASMCs from PAH patients were grown in 9% serum and treated with IP receptor agonists ± 1 μM RO-1138452 (IP receptor antagonist) for 1hr (cyclic AMP) or 96hr (cell proliferation). Cyclic AMP was assessed using an ELISA and cell proliferation using an MTS assay. Distal PAs from control patients (mean age 66yr) were mounted in a myograph and pre-tensioned to an equivalent of ∼22 mmHg (3K Pascal) before being constricted with U46619 (thromboxane mimetic; 100nM). The concentration (EC50) producing the half maximal response (Emax) was determined. Results: Iloprost, APD811, MRE-269 (selexipag metabolite) and treprostinil increased cyclic AMP (EC50 17, 252, 340, 550 nM, respectively). Emax was lower (P<0.001; n=5) for all three agents (64, 45, 25%, respectively) compared with treprostinil. In proliferation assays, APD811 was 10 fold more potent (14 nM) than MRE-269 (145 nM) and Emax were lower for both compared to treprostinil (57% versus 89%). RO-1138452 (1 μM) abolished agonist-induced cAMP generation and the antiproliferative effects of APD811 and MRE-269. In contrast, the antiproliferative effects of treprostinil and iloprost were weakly inhibited by RO-1138452. In PAs, APD811 produced a significantly (P<0.001, n=5–8) greater relaxation (Emax 98%) compared to iloprost (Emax 84%), treprostinil (Emax 71%) or MRE-296 (Emax 59%) and was more potent than MRE-269 (EC50 449nM versus 1579 nM) but similar to iloprost (EC50 650 nM) or treprostinil (EC50=320 nM).  Conclusions: APD811 and MRE-269 behave as selective, but partial IP receptor agonists, whereas iloprost and treprostinil can inhibit cell proliferation through IP-receptor independent pathways. In all assays APD811 produced superior effects to MRE-269 and had a favourable vasodilator profile compared with iloprost and treprostinil. Acknowledgement/Funding: Funding for this study was provided by Arena Pharmaceuticals, Inc.  

APD811 (ralinepag), a novel non-prostanoid IP receptor agonist, has potent antiproliferative and vasorelaxant properties in human pulmonary artery

http://discovery.ucl.ac.uk/10067544/1/Abstract%20ESC%202017%20Acepted%20version.pdf

APD811 (ralinepag), a novel non-prostanoid IP receptor agonist, has potent antiproliferative and vasorelaxant properties in human pulmonary artery

Abstract

Similar works

Full text

Available Versions

UCL Discovery