Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model
Graphical abstract
In this letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Aβ by 28% and 32% in the cortex and CSF, respectively, in the wild type preclinical Hartley guinea pig animal model when dosed orally at 30 mpk BID for 2.5 days.
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Acknowledgment
We would like to thank Louis Brogley, Luke Tso, John A. Tucker, Varghese John, Jay S. Tung, Michael A. Pleiss, Danny Tam, Cristian Cabrera, Danielle Pappas, Jim Miller, Nancy Jewett, Jackie Kwong, Ann Qin, Lee Latimer, Shawn Gauby, and Colin Lorentzen for their contributions to this work.
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