Can be expected over the GI50 concentrations for 4 h after ip twice t Adjusted dose of 50 mg / kg IP 540 or 25 mg / kg IP 620 be. Moreover, the concentrations of about 3.5 hours after GI50 50 mg / 620 kg IP. Target modulation and antitumor activity t of PI 540 and produced 620 PI-103 in U87MG glioblastoma xenografts PI on the basis of the above results, pharmacokinetics, athymic mice M Which xenografts of U87MG glioblastoma cells re U to inhibit short courses of treatment with IP IP 540 or 620 for four days their R Ability, phosphatidylinositol 3-kinase in the tumor tissue in vivo study. Electrochemiluminescence immunoassay tumors showed that the Akt phosphorylation was inhibited in a dose of fa Dependence Ngig and Transient Dependent.
3C and D show that phosphorylation at Ser473 and Thr308 AKT AKT was inhibited by 50% after 1 hour PI 540 with the two regimes. Remained in the basement To check values W During the 8 hours of time for these biomarkers, although the recovery was significantly after 4 hours in the time of submission of 50 mg / kg for the phosphorylation of Ser473 AKT. Downstream Rts are of AKT, two Anh Length a temporary inhibition of phosphorylation of p70S6K given, but there was no detectable inhibition of phosphorylation of GSK3. PI 620 also inhibited the phosphorylation of AKT at both locations in one hour, although the recovery was completed in 4 hours at the low doses used in this connection. The temporary inhibition of the phosphorylation of GSK3 and p70S6K was also observed.
In a subsequent study on the effectiveness, IP 540 and IP 620 were ip at 50 mg / kg dosed once or twice a day and 620 PI was also at 25 mg / kg twice t Resembled M athymic mice for 14 days With U87MG glioblastoma xenografts acquired rights. At these doses was well tolerated, the rate of tumor growth was significantly slowed and final T / C values were 33.9% and 44.8% IP 540 and IP 620 26.7% dosed at 50 mg / kg and 25 mg uid / kg twice t resembled, respectively. The pharmacokinetics of GDC 0941, the rapid plasma clearance and tissue IP-103 was the result of the rapid glucuronidation of phenolic group. Despite the Feedb Length in mouse and human microsomal metabolism of PI 540 and PI 620 103 as compared to a PI was significantly more observed in vivo glucuronidation. This is what explained Rt rapid clearance in the previous section.
To remove this metabolic liability, various phenol were synthesized and tested isosteres. The indazole derivative GDC 0941, which also showed the piperazine sulfonyl solubilization of microsomal metabolism Descr Nkt, resulting in oral bioavailability of 78%, total weight Tzlich to its strong inhibitory effect on the phosphatidylinositol 3-kinase. 6A shows the pharmacokinetics of GDC 0941 po at 75 mg / kg to athymic M Administered mice with xenografts of U87MG glioblastoma. GDC 0941 was rapidly absorbed with a Cmax concerning Post administration gt 30 minutes. The tumor was also distributing quickly with a Cmax, at the same time. Although the tumor plasma-money ratio was about 0.8 have entered these properties Born tumor post administration of the compound concentrations well above the GI50 to 6 hours. GDC 0941 was athymic M Mice once t Possible po 50 mg / kg or 150 mg / kg administered for 4 days and 3 xenog phosphatidylinositol kinase activation in U87MG tumor