Rational design of novel, potent piperazinone and imidazolidinone BACE1 inhibitors.
Guided by structure-based design, we synthesized two novel series of potent inhibitors of BACE1 and generated extensive SAR around both the prime and non-prime side binding pockets. The key feature of both series is a cyclic amine motif specifically crafted to achieve interactions with both the flap and with the S2' pocket.
Cumming
J N
JN
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. jared.cumming@spcorp.com
Le
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Babu
S
S
Carroll
C
C
Chen
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Favreau
L
L
Gaspari
P
P
Guo
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T
Hobbs
D W
DW
Huang
Y
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Iserloh
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Kennedy
M E
ME
Kuvelkar
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Li
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Lowrie
J
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McHugh
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NA
Ozgur
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L
Pan
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Parker
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Saionz
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Stamford
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Strickland
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Tadesse
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D
Voigt
J
J
Wang
L
L
Wu
Y
Y
Zhang
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Zhang
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D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D048289:Imidazolidines; D010879:Piperazines; C004916:ethylene urea; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human