Table 3 In vitro potency of LEO 134310 and comparison to CP and BMV. GR agonist-induced transactivation of mouse mammary tumour virus (MMTV) promoter in HeLa cells and PMA-induced, GR-mediated transrepression of human Matrix Metallopeptidase 1 (MMP1) promoter in HeLa cells of LEO 134310 (n = 2), its major metabolite, LEO 134998 (n = 2), CP (n = 6–7) and BMV (n = 1–2). Inhibition of LPS-induced TNF-alpha release in PBMCsa isolated from Human, Mouse, and Pig whole blood. LEO 134310 (n = 15, 2, 2), its major metabolite, LEO 134998 (n = 10, 3, 5), CP (n = 17, 4, 4) and BMV (n = 15, 2, 2). Geometric mean (95% confidence intervals within brackets for n > 2. For n = 2 individual results are shown. *p < 0.05 compared to LEO 134310.
Compound | Transactivation EC50 (nM) Emax (%) | Transrepression EC50 (nM) Emax (%) | Humana EC50 (nM) Emax (%) | Mousea EC50 (nM) Emax (%) | Piga EC50 (nM) Emax (%) |
|---|---|---|---|---|---|
CP | 0.25 (0.078–0.83) 110 | 0.064 (0.029–0.15) 90 | 0.52 (0.22–1.2) 79 | 0.15 (0.053–0.43) 95 | 0.38 (0.27–0.54) 95 |
BMV | 2.6 (n = 1) 120 | 0.57 (0.40, 0.82) 78 | 3.2 (1.5–6.7) 79 | 0.22 (0.18, 0.27) 95 | 1.5 (1.2, 1.8) 99 |
LEO 134310 | 410 (340, 480) 95 | 1.2 (1.2, 1.3) 100 | 2.3 (0.61–8.4) 77 | 0.58 (0.25, 1.3) 102 | 3.2 (1.4–7.2) 96 |
LEO 134998 | 560 (520, 590) 88 | 46* (41, 50) 98 | 260* (77–902) 75 | 35* (22–58) 100 | 210* (140–330) 93 |
