ABSTRACT
In an effort to identify kinase inhibitors with dual KDR/Aurora B activity and improved aqueous solubility compared to the Abbott dual inhibitor ABT-348, a series of novel pyrazole pyrimidines structurally related to kinase inhibitor AS703569 were prepared. SAR work provided analogs with significant cellular activity, measureable aqueous solubility and moderate antitumor activity in a mouse tumor model after weekly ip dosing. Unfortunately these compounds were pan-kinase inhibitors that suffered from narrow therapeutic indices which prohibited their use as antitumor agents.
Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazoles/chemistry , Pyrimidines/chemistry , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Amination , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Aurora Kinase B , Aurora Kinases , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Models, Molecular , Molecular Structure , Pyrimidines/pharmacology , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
The effect of rifampin, a cytochrome P450 3A4 inducer, on the pharmacokinetics of atrasentan was assessed in 12 healthy male subjects in an open-label study. Single doses of atrasentan 10 mg were administered orally on days 1 and 12. Rifampin 600 mg was given once daily from days 4 through 14. On day 12, atrasentan and rifampin were administered simultaneously. Blood samples were collected before and during 72 hours after each atrasentan dose. On average, rifampin increased atrasentan peak plasma concentrations by 150% and reduced its terminal half-life by 77% (P<.05), without affecting the AUC or peak time of atrasentan. Rifampin may affect atrasentan pharmacokinetics by acting as both an inhibitor of organic anion transporting polypeptide-mediated hepatic uptake of atrasentan and an inducer of atrasentan metabolism. The effect of rifampin on atrasentan pharmacokinetics may depend on the time of rifampin administration relative to that of atrasentan.
