Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model

doi:10.1016/j.bmcl.2010.08.102

Bioorganic & Medicinal Chemistry Letters

Volume 20, Issue 21, 1 November 2010, Pages 6231-6236

https://doi.org/10.1016/j.bmcl.2010.08.102 Get rights and content

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 Αβ by 28% and 32% in the cortex and CSF, respectively, in the preclinical wild type Hartley guinea pig animal model when dosed orally at 30 mpk BID for 2.5 days.

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.

Section snippets

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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Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model

Abstract

Graphical abstract

Section snippets

Acknowledgment

Annu. Rev. Neurosci.

Drug Dev. Res.

Expert Opin. Drug Discov.

Med. Res. Rev.

J. Med. Chem.

Nature

Neurobiol. Aging

Nat. Rev. Mol. Cell Biol.

Curr. Top. Med. Chem.

Proc. Natl. Acad. Sci. U.S.A.

Proc. Natl. Acad. Sci. U.S.A.

Science

Proc. Natl. Acad. Sci. U.S.A.

Curr. Top. Med. Chem.

Pharm. Res.

J. Med. Chem.

Synlett

Chem. Comm.

Tetrahedron Lett.

Drug Metab. Dispos.

Drug Metab. Lett.

Curr. Drug Metab.

Curr. Drug Metab.

Drug Metab. Dispos.

Expert Opin. Drug Metab. Toxicol.

Drug Metab. Dispos.

Curr. Drug Metab.

Clin. Pharmacokinet.

J. Biol. Chem.

Biochemistry

J. Med. Chem.

Alzheimers Dement.

N. Engl. J. Med.

Lancet

Nat. Med.

Lancet

Science

Proc. Natl. Acad. Sci. U.S.A.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

J. Pharmacol. Exp. Ther.

J. Neurochem.

J. Neurochem.

Nat. Rev. Drug Discov.

Nat. Rev. Neurol.

Expert Rev. Neurother.

Alzheimers Dement.

Mol. Neurobiol.

Curr. Top. Med. Chem.

Nat. Rev. Neurosci.

N. Engl. J. Med.

Curr. Top. Med. Chem.

J. Biol. Chem.

Toxicol. Sci.

J. Biol. Chem.

Proc. Natl. Acad. Sci. U.S.A.

Proc. Natl. Acad. Sci. U.S.A.

Nat. Neurosci.

Nat. Neurosci.

Hum. Mol. Genet.

Neurobiol. Dis.