Acylguanidine inhibitors of beta-secretase: optimization of the pyrrole ring substituents extending into the S1 and S3 substrate binding pockets.
Proteolytic cleavage of amyloid precursor protein by beta-secretase (BACE-1) and gamma-secretase leads to formation of beta-amyloid (A beta) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels of A beta and thus have therapeutic potential for treating Alzheimer's disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5-diphenyl-pyrrol-1-yl)-acetyl]guanidine (3.a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S(1) and S(2') pockets leading to submicromolar BACE-1 inhibitors.
Cole
Derek C
DC
Chemical & Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. coledc@wyeth.com
Stock
Joseph R
JR
Chopra
Rajiv
R
Cowling
Rebecca
R
Ellingboe
John W
JW
Fan
Kristi Y
KY
Harrison
Boyd L
BL
Hu
Yun
Y
Jacobsen
Steve
S
Jennings
Lee D
LD
Jin
Guixian
G
Lohse
Peter A
PA
Malamas
Michael S
MS
Manas
Eric S
ES
Moore
William J
WJ
O'Donnell
Mary-Margaret
MM
Olland
Andrea M
AM
Robichaud
Albert J
AJ
Svenson
Kristine
K
Wu
JunJun
J
Wagner
Eric
E
Bard
Jonathan
J
D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D006146:Guanidines; C527343:N-(2-(2,5-diphenyl-pyrrol-1-yl)-acetyl)guanidine; D011758:Pyrroles; D053829:Amyloid Precursor Protein Secretases