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.
Merck Research Laboratories, Kenilworth, NJ 07033, USA. ruo.xu@merck.com
Ruo
R
Xu
David
D
Cole
Ted
T
Asberom
Tom
T
Bara
Chad
C
Bennett
Duane A
DA
Burnett
John
J
Clader
Martin
M
Domalski
William
W
Greenlee
Lynn
L
Hyde
Hubert
H
Josien
Hongmei
H
Li
Mark
M
McBriar
Brian
B
McKittrick
Andrew T
AT
McPhail
Dmitri
D
Pissarnitski
Li
L
Qiang
Murali
M
Rajagopalan
Thavalakulamgar
T
Sasikumar
Jing
J
Su
Haiqun
H
Tang
Wen-Lian
WL
Wu
Lili
L
Zhang
Zhiqiang
Z
Zhao
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