N-{3-[2-(4-alkoxyphenoxy)thiazol-5-yl]-1-methylprop-2-ynyl}carboxy derivatives as acetyl-coA carboxylase inhibitors--improvement of cardiovascular and neurological liabilities via structural modifications.
A preliminary safety evaluation of ACC2 inhibitor 1-(S) revealed serious neurological and cardiovascular liabilities of this chemotype. A systematic structure-toxicity relationship study identified the alkyne linker as the key motif responsible for these adverse effects. Toxicogenomic studies in rats showed that 1-(R) and 1-(S) induced gene expression patterns similar to that seen with several known cardiotoxic agents such as doxorubicin. Replacement of the alkyne with alternative linker groups led to a new series of ACC inhibitors with drastically improved cardiovascular and neurological profiles.
Gu
Yu Gui
YG
Global Pharmaceutical Research and Development, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, Illinois 60064, USA. yu-gui.y.gu@abbott.com
Weitzberg
Moshe
M
Clark
Richard F
RF
Xu
Xiangdong
X
Li
Qun
Q
Lubbers
Nathan L
NL
Yang
Yi
Y
Beno
David W A
DW
Widomski
Deborah L
DL
Zhang
Tianyuan
T
Hansen
T Matthew
TM
Keyes
Robert F
RF
Waring
Jeffrey F
JF
Carroll
Sherry L
SL
Wang
Xiaojun
X
Wang
Rongqi
R
Healan-Greenberg
Christine H
CH
Blomme
Eric A
EA
Beutel
Bruce A
BA
Sham
Hing L
HL
Camp
Heidi S
HS
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D007262:Infusions, Intravenous; D008297:Male; D009206:Myocardium / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry
D013844:Thiazoles; D000103:Acetyl-CoA Carboxylase