Strategies toward improving the brain penetration of macrocyclic tertiary carbinamine BACE-1 inhibitors

Keith P Moore; Hong Zhu; Hemaka A Rajapakse; Georgia B McGaughey; Dennis Colussi; Eric A Price; Sethu Sankaranarayanan; Adam J Simon; Nicole T Pudvah; Jerome H Hochman; Timothy Allison; Sanjeev K Munshi; Samuel L Graham; Joseph P Vacca; Philippe G Nantermet

doi:10.1016/j.bmcl.2007.08.040

Strategies toward improving the brain penetration of macrocyclic tertiary carbinamine BACE-1 inhibitors

Bioorg Med Chem Lett. 2007 Nov 1;17(21):5831-5. doi: 10.1016/j.bmcl.2007.08.040. Epub 2007 Aug 23.

Authors

Keith P Moore¹, Hong Zhu, Hemaka A Rajapakse, Georgia B McGaughey, Dennis Colussi, Eric A Price, Sethu Sankaranarayanan, Adam J Simon, Nicole T Pudvah, Jerome H Hochman, Timothy Allison, Sanjeev K Munshi, Samuel L Graham, Joseph P Vacca, Philippe G Nantermet

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA. [email protected]

PMID: 17827011
DOI: 10.1016/j.bmcl.2007.08.040

Abstract

This letter describes replacements for the P3 amide moiety present in previously reported tertiary carbinamine macrolactones. Although P-gp efflux issues associated with these amide-macrolactones were solved and full brain penetration was measured in one case, potency was compromised in the process.

MeSH terms

Amines / pharmacokinetics*
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Brain / metabolism*
Crystallography, X-Ray
Enzyme Inhibitors / pharmacokinetics*
Models, Molecular

Substances

Amines
Enzyme Inhibitors
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human