Discoveryof 2-{3-[2-(1-Isopropyl-3-methyl-1H-1,2–4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide(GDC-0032): A β-Sparing Phosphoinositide 3-KinaseInhibitor with High Unbound Exposure and Robust in Vivo AntitumorActivity

Dysfunctional signalingthrough the phosphoinositide 3-kinase (PI3K)/AKT/mTORpathway leads to uncontrolled tumor proliferation. In the course ofthe discovery of novel benzoxepin PI3K inhibitors, we observed a strongdependency of in vivo antitumor activity on the free-drug exposure.By lowering the intrinsic clearance, we derived a set of imidazobenzoxazepincompounds that showed improved unbound drug exposure and effectivelysuppressed growth of tumors in a mouse xenograft model at low drugdose levels. One of these compounds, GDC-0032 (11l),was progressed to clinical trials and is currently under phase I evaluationas a potential treatment for human malignancies. [ABSTRACT FROM AUTHOR]