title: PRX-08066, a novel 5-hydroxytryptamine receptor 2B antagonist, reduces monocrotaline-induced pulmonary arterial hypertension and right ventricular hypertrophy in rats.
abstract: Pulmonary arterial hypertension (PAH) is a life-threatening disease that results in right ventricular failure. 5-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluorobenzonitrile monofumarate (PRX-08066) is a selective 5-hydroxytryptamine receptor 2B (5-HT2BR) antagonist that causes selective vasodilation of pulmonary arteries. In the current study, the effects of PRX-08066 were assessed by using the monocrotaline (MCT)-induced PAH rat model. Male rats received 40 mg/kg MCT or phosphate-buffered saline and were treated orally twice a day with vehicle or 50 or 100 mg/kg PRX-08066 for 5 weeks. Pulmonary and cardiac functions were evaluated by hemodynamics, heart weight, magnetic resonance imaging (MRI), pulmonary artery (PA) morphology, and histology. Cardiac MRI demonstrated that PRX-08066 (100 mg/kg) significantly (P < 0.05) improved right ventricular ejection fraction. PRX-08066 significantly reduced peak PA pressure at 50 and 100 mg/kg (P < 0.05 and < 0.01, respectively) compared with MCT control animals. PRX-08066 therapy also significantly reduced right ventricle (RV)/body weight and RV/left ventricle + septum (P < 0.01 and < 0.001, respectively) compared with MCT-treated animals. Morphometric assessment of pulmonary arterioles revealed a significant reduction in medial wall thickening and lumen occlusion associated with both doses of PRX-08066 (P < 0.01). The 5-HT2BR antagonist PRX-08066 significantly attenuated the elevation in PA pressure and RV hypertrophy and maintained cardiac function. Pulmonary vascular remodeling was also diminished compared with MCT control rats. PRX-08066 prevents the severity of PAH in the MCT rat model.
authors.affiliation: Department of Pediatrics, Powell Gene Therapy Center, University of Florida, Gainesville, Florida 32610-0266, USA.
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Porvasnik
authors.forename: Sean
authors.initials: S
authors.lastname: Germain
authors.forename: Jennifer
authors.initials: J
authors.lastname: Embury
authors.forename: Kimberley S
authors.initials: KS
authors.lastname: Gannon
authors.forename: Vincent
authors.initials: V
authors.lastname: Jacques
authors.forename: Justin
authors.initials: J
authors.lastname: Murray
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.forename: Faris
authors.initials: F
authors.lastname: Al-Mousily
mesh_terms: D000818:Animals; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D016686:Monocrotaline; D009206:Myocardium / Q000473:pathology; D009929:Organ Size; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D011743:Pyrimidines / Q000097:blood / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058830:Serotonin 5-HT2 Receptor Antagonists; D013876:Thiophenes / Q000097:blood / Q000627:therapeutic use*
chemical_list: C551465:5-((4-(6-chlorothieno(2,3-d)pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluorobenzonitrile; D011743:Pyrimidines; D058830:Serotonin 5-HT2 Receptor Antagonists; D013876:Thiophenes; D016686:Monocrotaline