Discovery and initial optimization of 5,5'-disubstituted aminohydantoins as potent beta-secretase (BACE1) inhibitors.
8,8-Diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S(1) to the S(3) pocket.
Nowak
Pawel
P
Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, United States. nowakp@wyeth.com
Cole
Derek C
DC
Aulabaugh
Ann
A
Bard
Jonathan
J
Chopra
Rajiv
R
Cowling
Rebecca
R
Fan
Kristi Y
KY
Hu
Baihua
B
Jacobsen
Steve
S
Jani
Minakshi
M
Jin
Guixan
G
Lo
Mei-Chu
MC
Malamas
Michael S
MS
Manas
Eric S
ES
Narasimhan
Rani
R
Reinhart
Peter
P
Robichaud
Albert J
AJ
Stock
Joseph R
JR
Subrath
Joan
J
Svenson
Kristine
K
Turner
Jim
J
Wagner
Erik
E
Zhou
Ping
P
Ellingboe
John W
JW
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D006827:Hydantoins; D007093:Imidazoles; D053829:Amyloid Precursor Protein Secretases