Design, synthesis, and crystal structure of hydroxyethyl secondary amine-based peptidomimetic inhibitors of human beta-secretase.
The design and synthesis of a novel series of potent and cell permeable peptidomimetic inhibitors of the human beta-secretase (BACE) are described. These inhibitors feature a hydroxyethyl secondary amine isostere and a novel aromatic ring replacement for the C-terminus. The crystal structure of BACE in complex with this hydroxyethyl secondary amine isostere inhibitor is also presented.
Maillard
Michel C
MC
Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, California 94080, USA.
Hom
Roy K
RK
Benson
Timothy E
TE
Moon
Joseph B
JB
Mamo
Shumeye
S
Bienkowski
Michael
M
Tomasselli
Alfredo G
AG
Woods
Danielle D
DD
Prince
D Bryan
DB
Paddock
Donna J
DJ
Emmons
Thomas L
TL
Tucker
John A
JA
Dappen
Michael S
MS
Brogley
Louis
L
Thorsett
Eugene D
ED
Jewett
Nancy
N
Sinha
Sukanto
S
John
Varghese
V
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D010795:Phthalic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
D016564:Amyloid beta-Protein Precursor; C518309:N-(1-(3,5-difluorobenzyl)-2-hydroxy-3-(3-iodobenzylamino)propyl)-5-methyl-N',N'-dipropylisophthalamide; D010455:Peptides; D010795:Phthalic Acids; D053829:Amyloid Precursor Protein Secretases