Lead optimization and modulation of hERG activity in a series of aminooxazoline xanthene β-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors.
The optimization of a series of aminooxazoline xanthene inhibitors of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aβ lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust Aβ reduction in a rat pharmacodynamic model (78% Aβ reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.
Departments of Therapeutic Discovery, ‡Neuroscience, §Molecular Structure and Characterization, ∥Pharmacokinetics and Drug Metabolism, and ⊥Comparative Biology and Safety Sciences, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, One Amgen Center Drive, Thousand Oaks, California 91320, and 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
Oleg
O
Epstein
Marian C
MC
Bryan
Alan C
AC
Cheng
Katayoun
K
Derakhchan
Thomas A
TA
Dineen
Dean
D
Hickman
Zihao
Z
Hua
Jason B
JB
Human
Charles
C
Kreiman
Isaac E
IE
Marx
Matthew M
MM
Weiss
Robert C
RC
Wahl
Paul H
PH
Wen
Douglas A
DA
Whittington
Stephen
S
Wood
Xiao Mei
XM
Zheng
Robert T
RT
Fremeau
Ryan D
RD
White
Vinod F
VF
Patel
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010081:Oxazolone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis*; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014966:Xanthenes / Q000138:chemical synthesis* / Q000494:pharmacology
D051638:Ether-A-Go-Go Potassium Channels; D011480:Protease Inhibitors; D014966:Xanthenes; D010081:Oxazolone; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human