AZD1981 is a powerful and selective antagonist of CRTh2, effectively competing with radio-labelled PGD2 for binding to the human DP2 receptor, exhibiting a high level of potency (pIC50 = 8.4)[1]. Further, in a guinea pig hind limb model, AZD1981 at 10 nM markedly reduced DK-PGD2-driven eosinophil mobilization by about 50%, a suppression that was complete at 100 nM[1]. AZD1981 demonstrated efficient cross-species DP2 receptor binding activity in mice, rats, guinea pigs, rabbits, and dogs. However, mouse, rat, and rabbit cell systems did not exhibit a response to DP2 agonists, whereas guinea pig and dog systems did, with AZD1981 inhibiting DP2-mediated changes in eosinophil shape and migration from bone marrow, particularly noted in guinea pigs[1]. No positive clinical outcomes were observed with the use of AZD1981 at a dosage of 1000 mg twice daily over a four-week period in individuals with moderate to severe COPD, although the drug was generally well-received without raising safety issues[3].
体外研究
In vitro, AZD1981 demonstrated the ability to displace the binding of [3H]PGD2 in a concentration-dependent manner, achieving a mean pIC50 value of 8.4 ± 0.1 across 25 tests, with the geometric mean IC50 standing at 4 nM. AZD1981 displayed negligible binding to human DP1 receptors, evidenced by a minimal average displacement of [3H]PGD2-specific binding by 27% (ranging from 14-50%) at a maximal tested concentration of 10 μM. When compared to its binding efficacy to DP2, AZD1981 was found to be 10 times more selective than rat aldose reductase and 1700 times more selective than rat steroid 5α-reductase. In studies involving eosinophils, a singular dose of 1 μM of AZD1981 led to a significant (20-fold) increase in the displacement of the 15R-methyl PGD2 E/[A] curve without affecting the peak response. This prompted an examination using a sub-maximal agonist concentration (1 μM), through which AZD1981 inhibited eosinophil migration in a concentration-dependent manner, with a pIC50 of 7.6 ± 0.1[1].
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