Discovery of 2-{3-[2-(1-Isopropyl-3-methyl-1 H-1, 2–4-triazol-5-yl)-5, 6-dihydrobenzo [f] imidazo [1, 2-d][1, 4] oxazepin-9-yl]-1 H-pyrazol-1-yl}-2-methylpropanamide ( …

…, M Baumgardner, N Blaquiere, E Bradley…

Index: 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, 2013 , vol. 56, # 11 p. 4597 - 4610

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Citation Number: 42

Abstract

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 ...