Setipiprant

The aim of this study was to investigate aldose reductase inhibitory action of setipiprant as a potential additional mechanism contributing to its anti-inflammatory action. Aldose reductase activity was determined by spectrophotometric measuring of NADPH consumption. Setipiprant was found to inhibit aldose reductase/NADPH-mediated reduction of 4-hydroxynonenal, 4-hydroxynonenal glutathione and prostaglandin H2 substrates, all relevant to the process of inflammation. Molecular modeling simulations into the aldose reductase inhibitor binding site revealed an interaction pattern of setipiprant. Considering multifactorial etiology of inflammatory pathologies, it is suggested that, in addition to the antagonizing prostaglandin D2 receptor, inhibition of aldose reductase may contribute to the reported anti-inflammatory action of setipiprant.

Prostaglandin D₂ (PGD₂) released by degranulating mast cells is believed to play a key role in orchestrating mechanisms of inflammation in allergies and asthma. The biological effects of PGD₂ are mediated by D-prostanoid (DP1), CRTH2 (DP2), and thromboxane prostanoid (TP) receptors. The CRTH2 receptor is involved in induction of migration and activation of T helper type 2 (Th₂) lymphocytes, eosinophils, and basophils; up-regulation of adhesion molecules; and promotion of pro-inflammatory Th₂-type cytokines (interleukin [IL]-4, 5, 13), whereas the DP receptor is associated with relaxation of smooth muscles, vasodilation, inhibition of cell migration, and apoptosis of eosinophils. A number of CRTH2/PGD₂ receptor antagonists have been investigated in asthma and allergic diseases. The CRTH2 antagonist (OC000459) or dual CRTH2 and TP receptor antagonist (ramatroban) were effective in reducing eosinophilia, nasal mucosal swelling, and clinical symptoms of allergic rhinitis, with the latter drug registered for clinical use in this indication. OC000459 and setipiprant reduced the late but not early phase of response in an allergen challenge in atopic asthmatics. In persistent asthma, some molecules induced limited improvement in lung function, quality of life, and asthma symptoms (OC000459, BI671800), but in other trials with AMG 853 and AZ1981 these findings were not confirmed. The clear discrepancy between animal studies and clinical efficacy of CRTH2 antagonism in allergic rhinitis, and lack of efficacy in a general cohort of asthmatics, highlight the issue of patient phenotyping. There is no doubt that the PGD₂/CATH2/DP1 pathway plays a key role in allergic inflammation and further studies with selective or combined antagonisms in well defined cohorts of patients are needed.