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PRX-08066: A Potent 5-HT2B Receptor Antagonist with a dual disease modifying/vasodilating mechanism for the Treatment of Pulmonary Hypertension

Sharon Shacham

Pini Orbach

Yael Marantz

S. Reddy

Joseph Rutkowski

Oren Becker

Luc Maroteaux

Michael Ward

Hwee Teoh

Jean-Marie Launay


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Conference: 2006 International PHA Conference and Scientific Sessions

Release Date: 06.23.2006

Presentation Type: Abstracts

Sharon Shacham1, Pini Orbach1, Yael Marantz1, Sekar Reddy1, Joseph Rutkowski1, Oren Becker1, Luc Maroteaux2, Michael Ward3, Hwee Teoh3, Jean-Marie Launay4, Nicolas Delacotte5, Georges-Alexendre Guérin4and Silvia Noiman1

1Predix Pharmaceuticals, Lexington, MA, 2INSERM U616, Hôpital Pitié-Salpetrière, PARIS, France, 4St Michael’s HospitalToronto, Canada, 4Service de Biochimie Hôpital Lariboisière, PARIS France, 5BioQuanta, Paris, France

Pulmonary Arterial Hypertension (PAH) is characterized by the elevation of mean pulmonary arterial pressures, accompanied by pulmonary vascular hyperplasia and progressive narrowing of the blood vessels of the lungs. Recently, several studies have suggested a role for serotonin 5-HT in the etiology and progression of PAH. By activating its cognate receptors, 5-HT has a dual effect  on  the  pulmonary  circulation,  contributing  to  both  vasoconstriction  and  vascular remodeling (reviewed in (Farber & Loscalzo 2004). Pulmonary arteries express several 5-HT receptors including 5-HT1B, 5-HT2A, 5-HT2B and 5-HT7 receptors.

The 5-HT2B receptor (5-HT2BR) expression is  elevated in  murine and human PAH tissue relative to normal pulmonary arteries.  We have recently demonstrated that 5-HT2BR expression is selectively increased in arteries of rats that were exposed to hypoxic conditions for 16-48 hours, while no changes in 5-HT2BR expression was observed in the aorta or mesenteric arteries Furthermore, we found that BW 723C86, a potent and selective 5-HT2BR agonist had no effect on the vascular tone of isolated rings from normoxic rats while inducing a potent vasoconstriction on hypoxic arterial rings, suggesting that the 5-HT2BR is involved in enhanced vasoconstrictor response to 5-HT under hypoxic conditions. Together, these results suggest that 5-HT2BR antagonists can induce selective and sustained pulmonary vasodilatation in patients with hypoxic or primary PAH without having a marked effect on systemic arterial pressure.

PRX-08066 is a highly potent (Ki ~ 1.7 nM) and selective (Ki > 100 fold for more than 55 receptors tested) 5-HT2BR antagonist. PRX-08066 had a potent, dose-dependent inhibitory effect on 5-HT induced contraction in pulmonary arterial rings of both hypoxic and normoxic rats, with an IC50 of <1 nM. Chronic exposure of mice and rats to hypoxia (10% O2 for 2-3 weeks) leads to substantial increase in structural remodeling of the pulmonary arteries and increased right ventricular systolic pressure (RVSP). PRX-08066 was found to induce significant dose-dependent decrease in RVSP in hypoxia-induced mouse and rat models of PAH (n>3), without affecting systemic blood pressure (SBP). Moreover, when tested in Fawn Hooded rat short-term hypoxic model (n=6), PRX-08066 (i.p. 50mg/kg) reduced the hypoxia-dependent increase in RVSP with no apparent affect on SBP.  These results suggest that PRX-08066 can induce selective relaxation of pulmonary arteries without affecting the systemic pressure.

In a series of in vitro studies designed to test the effect of PRX-08066 on the 5-HT-induced vascular muscularization, PRX-08066 inhibited the 5-HT-induced mitogen-activated protein kinase (MAPK) activation (IC50 ≈ 12nM) and markedly reduced thymidine incorporation (IC50

≈ 3nM) in Chinese Hamster Ovary (CHO) cells expressing the human 5-HT2BR. Chronic exposure of rats to hypoxia (10% O2) leads to an increase in RVSP and results in hypertrophy of the right ventricle (RV) as can be measured by weight of the RV to the weight of the left ventricle plus the septum (RV/[LV+ S]). Chronic administration of PRX-08066 inhibited the hypoxia induced increase in RV/LV+S ratio and reduced the RVSP without affecting SBP. These results suggest  that  PRX-08066  can  potentially  inhibit  the  pathologic  hypoxia-induced  vascular muscularization associated with PAH.

PRX-08066 has good bioavailability and the preclinical safety profile of PRX-08066, including assessment of cardiovascular and central nervous system safety demonstrates that PRX-08066 has a low order of acute toxicity. PRX-08066 is currently being investigated in clinical trials. These results suggest that PRX-08066 can potentially represent a novel approach to treat patients with pulmonary arterial hypertension.