Discovery of 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‑Kinase Inhibitor with High Unbound Exposure and Robust in Vivo Antitumor Activity

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Discovery of 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‑Kinase Inhibitor with High Unbound Exposure and Robust in Vivo Antitumor Activity

Ndubaku, Chudi O; Heffron, Timothy P; Staben, Steven T; Baumgardner, Matthew; Blaquiere, Nicole; Bradley, Erin; Bull, Richard; Do, Steven; Dotson, Jennafer; Dudley, Danette; Edgar, Kyle A; Friedman, Lori S; Goldsmith, Richard; Heald, Robert A; Kolesnikov, Aleksandr; Lee, Leslie; Lewis, Cristina; Nannini, Michelle; Nonomiya, Jim; Pang, Jodie; Price, Steve; Prior, Wei Wei; Salphati, Laurent; Sideris, Steve; Wallin, Jeffery J; Wang, Lan; Wei, BinQing; Sampath, Deepak; Olivero, Alan G

Journal of medicinal chemistry, 06/2013, Volume: 56, Issue: 11

Journal Article

Dysfunctional signaling through the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway leads to uncontrolled tumor proliferation. In the course of the discovery of novel benzoxepin PI3K inhibitors, we observed a strong dependency of in vivo antitumor activity on the free-drug exposure. By lowering the intrinsic clearance, we derived a set of imidazobenzoxazepin compounds that showed improved unbound drug exposure and effectively suppressed growth of tumors in a mouse xenograft model at low drug dose levels. One of these compounds, GDC-0032 (11l), was progressed to clinical trials and is currently under phase I evaluation as a potential treatment for human malignancies.

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