Efficacy of FP-025: A novel matrix metalloproteinase-12 (MMP-12) inhibitor in murine allergic asthma
Abstrakt
Asthma is a heterogeneous disease, as reflected by differences in age of onset, severity, treatment response and inflammatory profile. Matrix metalloprotease (MMP)-12 has been associated with inflammation in various subtypes of asthma.
In allergic asthma, MMP-12 activity has been implicated in the accumulation of neutrophils and eosinophils, in regulating macrophage functions and in the development of airway hyperresponsiveness (AHR). To date, the underlying mechanisms by which MMP-12 may drive asthma pathophysiology have not been defined, nor has inhibition of MMP-12 as a targeted therapy for asthma been assessed in humans.
FP-025 is a novel, potent, and highly selective non-hydroxamate inhibitor of MMP-12 with 90-fold selectivity over the closest family member (MMP-2) and two to three orders of magnitude over the seven other MMP family members. In an established mouse model of persistent house dust mite (HDM) allergic asthma, we explored the effect of increasing doses (0-100 mg/kg, daily for 7 days) of oral FP-025 on airway pathophysiology, with Prednisone (5 mg/kg) given intraperitoneally as control treatment.