3-(2-6-dichloro-3-5-dimethoxyphenyl)-1-(6-(4-(4-ethylpiperazin-1-yl)-phenylamino)pyrimidin-4-yl)-1-methylurea and Pulmonary-Arterial-Hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease associated with high morbidity and mortality, despite advances in medical therapy. We compared the effects of infigratinib (NVP-BGJ398), a new FGF receptor-1 inhibitor, with or without the PDE-5 inhibitor sildenafil, on vascular function and remodelling as well as on gene expression of signal transducers for receptors of TGF-β (Smads-1/2/4) and transcription factor of endothelial-mesenchymal transition (Twist-1) in established experimental PAH. Types I and III pro-collagen and TGF-β expressions in lung fibroblasts were analysed in vitro after the different treatments.. PAH was induced in male Wistar rats with monocrotaline. 14 days later, treatments [sildenafil (SIL), infigratinib (INF) or their combination (SIL+INF)] were given for another 14 days. On Day 28, echocardiography and haemodynamic assays were performed, and lungs and pulmonary vessels were removed for analysis by histology, immunohistochemistry and RT-PCR. Fibroblasts prepared from PAH lungs were also analysed for TGF-β and pro-collagen.. Only the combination of infigratinib and sildenafil significantly improved right ventricular systolic pressure and vascular remodelling parameters (right ventricular hypertrophy, smooth muscle α-actin, vessel wall thickness, and vascular collagen content). Infigratinib may act by reducing gene expression of Smads-1/4 and Twist-1 in lung tissue, as well as TGF-β and types I and III pro-collagen in lung fibroblasts.. In this model of monocrotaline-induced PAH, the combination of the new inhibitor of FGF receptor-1, infigratinib, and sildenafil effectively improved haemodynamics and decreased vascular remodelling.

Topics: Animals; Antihypertensive Agents; Injections, Intraperitoneal; Male; Monocrotaline; Phenylurea Compounds; Pulmonary Arterial Hypertension; Pyrimidines; Rats; Rats, Wistar; Receptor, Fibroblast Growth Factor, Type 1; Sildenafil Citrate