Iminoheterocycles as gamma-secretase modulators.
The synthesis of a novel series of iminoheterocycles and their structure-activity relationship (SAR) as modulators of gamma-secretase activity will be detailed. Encouraging SAR generated from a monocyclic core led to a structurally unique bicyclic core. Selected compounds exhibit good potency as gamma-secretase modulators, excellent rat pharmacokinetics, and lowering of Abeta42 levels in various in vivo models.
Caldwell
John P
JP
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States. john.caldwell@merck.com
Bennett
Chad E
CE
McCracken
Troy M
TM
Mazzola
Robert D
RD
Bara
Thomas
T
Buevich
Alexei
A
Burnett
Duane A
DA
Chu
Inhou
I
Cohen-Williams
Mary
M
Josein
Hubert
H
Hyde
Lynn
L
Lee
Julie
J
McKittrick
Brian
B
Song
Lixin
L
Terracina
Giuseppe
G
Voigt
Johannes
J
Zhang
Lili
L
Zhu
Zhaoning
Z
D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007097:Imines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007097:Imines; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases