Design of potent inhibitors of human beta-secretase. Part 2.
We describe an optimized series of acyclic hydroxyethylamine transition state isosteres of beta-secretase that incorporates a variety of P(2) side chains that yield potent inhibitors with excellent cellular activity. A 2.2A crystal structure of compound 13 is shown.
Freskos
John N
JN
Pfizer Inc., 700N. Chesterfield Pkwy., St. Louis, MO 63198, USA.
Fobian
Yvette M
YM
Benson
Timothy E
TE
Moon
Joseph B
JB
Bienkowski
Michael J
MJ
Brown
David L
DL
Emmons
Thomas L
TL
Heintz
Robert
R
Laborde
Alice
A
McDonald
Joseph J
JJ
Mischke
Brent V
BV
Molyneaux
John M
JM
Mullins
Patrick B
PB
Bryan Prince
D
D
Paddock
Donna J
DJ
Tomasselli
Alfredo G
AG
Winterrowd
Greg
G
D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002478:Cells, Cultured; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D002219:Carbamates; D011480:Protease Inhibitors; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases