Strategies toward improving the brain penetration of macrocyclic tertiary carbinamine BACE-1 inhibitors.
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.
Moore
Keith P
KP
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA. keith_moore2@merck.com
Zhu
Hong
H
Rajapakse
Hemaka A
HA
McGaughey
Georgia B
GB
Colussi
Dennis
D
Price
Eric A
EA
Sankaranarayanan
Sethu
S
Simon
Adam J
AJ
Pudvah
Nicole T
NT
Hochman
Jerome H
JH
Allison
Timothy
T
Munshi
Sanjeev K
SK
Graham
Samuel L
SL
Vacca
Joseph P
JP
Nantermet
Philippe G
PG
D000588:Amines / Q000493:pharmacokinetics*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001921:Brain / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D008958:Models, Molecular