β‑Secretase
(BACE1) Inhibitors with High
in Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer’s
Disease
Posted on 2013-05-23 - 00:00
An
extensive fluorine scan of 1,3-oxazines revealed the power of
fluorine(s) to lower the pKa and thereby
dramatically change the pharmacological profile of this class of BACE1
inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to
reduce significantly CSF Aβ40 and 42 in rats at oral doses as
low as 1 mg/kg. The effect was long lasting, showing a significant
reduction of Aβ40 and 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group
was virtually inactive in vivo.
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Hilpert, Hans; Guba, Wolfgang; Woltering, Thomas
J.; Wostl, Wolfgang; Pinard, Emmanuel; Mauser, Harald; et al. (2016). β‑Secretase
(BACE1) Inhibitors with High
in Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer’s
Disease. ACS Publications. Collection. https://doi.org/10.1021/jm400225m
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AUTHORS (22)
HH
Hans Hilpert
WG
Wolfgang Guba
TW
Thomas
J. Woltering
WW
Wolfgang Wostl
EP
Emmanuel Pinard
HM
Harald Mauser
AM
Alexander V. Mayweg
MR
Mark Rogers-Evans
RH
Roland Humm
DK
Daniela Krummenacher
TM
Thorsten Muser
CS
Christian Schnider
HJ
Helmut Jacobsen
LO
Laurence Ozmen
AB
Alessandra Bergadano
DB
David
W. Banner
RH
Remo Hochstrasser
AK
Andreas Kuglstatter
PD
Pascale David-Pierson
HF
Holger Fischer