Evaluation of WO-2014132220, selective PDGFR inhibitors for the treatment of pulmonary arterial hypertension

Abstract

Introduction: Pulmonary arterial hypertension (PAH) is a rare disease currently treated by a range of vasodilator agents and/or endothelin antagonists. Inhibition of platelet derived growth factor receptor (PDGFR) kinases has been suggested to provide an additional therapeutic modality, and clinical studies with the non-selective PDGFR inhibitor imatinib appear to validate this hypothesis. However, side-effects associated with a lack of selectivity suggest clinical utility requires the identification and development of selective PDGFR inhibitors.

Areas covered: This application claims derivatives and crystalline forms of two previously claimed PDGFR inhibitors and their use for the treatment of PAH. N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)ethylcarbamoyl)-2-methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide and N-(5-(2-(2,6-cis-dimethylpiperidin-1-yl)ethylcarbamoyl)-2-fluorophenyl)-7-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide have respective IC₅₀ values of 3 and 45 nM in a cellular proliferation assay.

Expert opinion: These two compounds are likely to be selective PDGFR inhibitors. The nature of this filing suggests that Novartis intends to develop at least one of these compounds for the treatment of PAH.

Keywords:

• platelet derived growth factor
• platelet derived growth factor receptor kinase inhibitor
• pulmonary arterial hypertension
• rare disease

Declaration of interest

The author has received an honorarium from Informa for the preparation of this manuscript. The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.