Design, synthesis, and SAR of macrocyclic tertiary carbinamine BACE-1 inhibitors.
This Letter describes the design and synthesis of tertiary carbinamine macrocyclic inhibitors of the beta-secretase (BACE-1) enzyme. These macrocyclic inhibitors, some of which incorporate novel P2 substituents, display a 2- to 100-fold increase in potency relative to the previously described acyclic analogs while affording greater stability.
Lindsley
Stacey R
SR
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA.
Moore
Keith P
KP
Rajapakse
Hemaka A
HA
Selnick
Harold G
HG
Young
Mary Beth
MB
Zhu
Hong
H
Munshi
Sanjeev
S
Kuo
Lawrence
L
McGaughey
Georgia B
GB
Colussi
Dennis
D
Crouthamel
Ming-Chih
MC
Lai
Ming-Tain
MT
Pietrak
Beth
B
Price
Eric A
EA
Sankaranarayanan
Sethu
S
Simon
Adam J
AJ
Seabrook
Guy R
GR
Hazuda
Daria J
DJ
Pudvah
Nicole T
NT
Hochman
Jerome H
JH
Graham
Samuel L
SL
Vacca
Joseph P
JP
Nantermet
Philippe G
PG
D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D003500:Cyclization; D015195:Drug Design; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000588:Amines; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human