tcsc0009391 MK-7246

MK-7246 is a potent and selective CRTH2 antagonist with a K_i of 2.5±0.5 nM.

IC50 & Target: Ki: 2.5±0.5 nM (CRTH2), 373±96 nM (Prostaglandin D, DP), 7668±2169 nM (Prostaglandin E2, EP₂), 3804±1290 nM (TXA2,TP)^[1]

In Vitro: The affinity and selectivity of MK-7246 for human CRTH2 and recombinant human prostanoid receptors is determined by equilibrium competition analysis using the relevant radioligands and cell membranes expressing the various receptors. MK-7246 competes for [³H]PGD₂ specific binding to cell membranes expressing recombinant human CRTH2 with high-affinity (K_i, 2.5 nM). MK-7246 displays a relatively high selectivity for CRTH2 with an affinity 149-fold lower for the DP receptor (K_i, 373±96 nM) and ≥1500-fold lower for the other prostanoid receptors (K_i, 7668±2169 nM for EP₂, 3804±1290 nM for TP). MK-7246 is also tested in a panel of 157 enzyme and receptor assays at concentrations up to 100 μM and small but significant activity is detected only on phosphodiesterase 1 (PDE1, IC₅₀=33.2 μM) and MAPK3 (ERK1, IC₅₀=49.4 μM)^[1].

In Vivo: Whether the inhibition of a clinically-relevant mechanism of allergic lung inflammation such as CRTH2 will lead to a suppression of inflammatory responses is investigated in A. alternata challenged Brown Norway rats (n=8 per group). Mast cell derived production of Prostaglandin D₂ (PGD₂) is believed to be a prime mediator of allergic inflammation. Since CRTH2 plays an important role in the early aspects of the allergic inflammation cascade, the effect of the CRTH2 antagonist is examined on A. alternate elicited pulmonary inflammatory responses. CRTH2 inhibitor MK-7246 is orally administered 1 h before and 23 h post-intratracheal instillation of the A. alternata. MK-7246 produces a dose dependent decrease in the number of eosinophils with a maximal inhibition of 74±5% in the 100 mg/kg group (P<0.05), IL-5 (80±12%) and IL-13 (76±14%) cytokines levels (P<0.05) ^[2].