Abstract

Deficiency of bone morphogenetic protein type II receptor (BMPRII) signaling has been  implicated  in  the  pathology  of  pulmonary  arterial  hypertension  (PAH). BMP ligands activate the receptor and also enhance BMPR2 transcription. A small molecule BMP upregulator with low toxicity may be a tractable approach to treat PAH.

   We used a dual reporter driven specifically in human embryonic stem cell (hESC)-derived endothelial cells (ECs) to identify a novel piperidine, BUR1 that increase endothelial Id1 expression. The sequential drug discovery steps from standard screening with micromolar level of BUR1 at 24 hours to scope the selective and effective dosage at nanomolar level. At early time point BUR1 shows the effects on BMPRII signalling, at later time point the effects of PTGS2 and other factors become apparent which could be beneficial for long term treatment. Further pharmacological studies in mice showed BUR1 has low toxicity.

  BUR1 not only restored BMPRII downstream signalling and modulated arachidonic acid pathway in the endothelial cells to improve pulmonary vascular remodelling, but also reversed cardiac output and TAPSE in Sugen 5416/hypoxia PAH model.

 In conclusion, we provide a small molecule compound that enhancing BMPRII signalling with low toxicity which might be useful for the treatment of PAH.