Design and synthesis of tricyclic sulfones as gamma-secretase inhibitors with greatly reduced Notch toxicity.
A novel series of tricyclic gamma-secretase inhibitors was designed and synthesized via a conformational analysis of literature compounds. The preliminary results have shown that compounds in this new series have much improved in vitro potency and in vivo profiles. More importantly, they have greatly reduced Notch related toxicity that was associated with previous gamma-secretase inhibitors.
Xu
Ruo
R
Merck Research Laboratories, Kenilworth, NJ 07033, USA. ruo.xu@merck.com
Cole
David
D
Asberom
Ted
T
Bara
Tom
T
Bennett
Chad
C
Burnett
Duane A
DA
Clader
John
J
Domalski
Martin
M
Greenlee
William
W
Hyde
Lynn
L
Josien
Hubert
H
Li
Hongmei
H
McBriar
Mark
M
McKittrick
Brian
B
McPhail
Andrew T
AT
Pissarnitski
Dmitri
D
Qiang
Li
L
Rajagopalan
Murali
M
Sasikumar
Thavalakulamgar
T
Su
Jing
J
Tang
Haiqun
H
Wu
Wen-Lian
WL
Zhang
Lili
L
Zhao
Zhiqiang
Z
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D051379:Mice; D008958:Models, Molecular; D051880:Receptors, Notch / Q000187:drug effects*; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D051880:Receptors, Notch; D013450:Sulfones; D053829:Amyloid Precursor Protein Secretases