Rapid P1 SAR of brain penetrant tertiary carbinamine derived BACE inhibitors.
This Letter describes the one pot synthesis of tertiary carbinamine 3 and related analogs of brain penetrant BACE-1 inhibitors via the alkylation of the Schiff base intermediate 2. The methodology developed for this study provided a convenient and rapid means to explore the P1 region of these types of inhibitors, where the P1 group is installed in the final step using a one-pot two-step protocol. Further SAR studies led to the identification of 10 which is twofold more potent in vitro as compared to the lead compound. This inhibitor was characterized in a cisterna magna ported rhesus monkey model, where significant lowering of CSF Abeta40 was observed.
Zhu
Hong
H
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
Young
Mary B
MB
Nantermet
Philippe G
PG
Graham
Samuel L
SL
Colussi
Dennis
D
Lai
Ming-Tain
MT
Pietrak
Beth
B
Price
Eric A
EA
Sankaranarayanan
Sethu
S
Shi
Xiao-Ping
XP
Tugusheva
Katherine
K
Holahan
Marie A
MA
Michener
Maria S
MS
Cook
Jacquelynn J
JJ
Simon
Adam
A
Hazuda
Daria J
DJ
Vacca
Joseph P
JP
Rajapakse
Hemaka A
HA
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001921:Brain / Q000201:enzymology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D008253:Macaca mulatta; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D010446:Peptide Fragments / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D010446:Peptide Fragments; D013449:Sulfonamides; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human