Acylguanidine inhibitors of beta-secretase: optimization of the pyrrole ring substituents extending into the S1' substrate binding pocket.
The proteolytic enzyme beta-secretase (BACE-1) produces amyloid beta (Abeta) peptide, the primary constituent of neurofibrillary plaques, implicated in Alzheimer's disease, by cleavage of the amyloid precursor protein. A small molecule inhibitor of BACE-1, (diaminomethylene)-2,5-diphenyl-1H-pyrrole-1-acetamide (1, BACE-1 IC(50)=3.7 microM), was recently described, representing a new small molecule lead. Initial SAR investigation demonstrated the potential of accessing the nearby S(3) and S(1)(') substrate binding pockets of the BACE-1 enzyme by building substituents off one of the phenyl substituents and guanidinyl functional group. We report here the optimization of guanidinyl functional group substituents on 1, leading to potent submicromolar BACE-1 inhibitors.
Jennings
Lee D
LD
Chemical & Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. jenninl@wyeth.com
Cole
Derek C
DC
Stock
Joseph R
JR
Sukhdeo
Mohani N
MN
Ellingboe
John W
JW
Cowling
Rebecca
R
Jin
Guixian
G
Manas
Eric S
ES
Fan
Kristi Y
KY
Malamas
Michael S
MS
Harrison
Boyd L
BL
Jacobsen
Steve
S
Chopra
Rajiv
R
Lohse
Peter A
PA
Moore
William J
WJ
O'Donnell
Mary-Margaret
MM
Hu
Yun
Y
Robichaud
Albert J
AJ
Turner
M James
MJ
Wagner
Erik
E
Bard
Jonathan
J
D000544:Alzheimer Disease / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019791:Guanidine / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D011758:Pyrroles / Q000737:chemistry*
D004791:Enzyme Inhibitors; D011758:Pyrroles; D053829:Amyloid Precursor Protein Secretases; D019791:Guanidine