Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2.
Screening Pfizer's compound library resulted in the identification of weak acetyl-CoA carboxylase inhibitors, from which were obtained rACC1 CT-domain co-crystal structures. Utilizing HTS hits and structure-based drug discovery, a more rigid inhibitor was designed and led to the discovery of sub-micromolar, spirochromanone non-specific ACC inhibitors. Low nanomolar, non-specific ACC-isozyme inhibitors that exhibited good rat pharmacokinetics were obtained from this chemotype.
Corbett
Jeffrey W
JW
Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. jmc1983mac@gmail.com
Freeman-Cook
Kevin D
KD
Elliott
Richard
R
Vajdos
Felix
F
Rajamohan
Francis
F
Kohls
Darcy
D
Marr
Eric
E
Zhang
Hailong
H
Tong
Liang
L
Tu
Meihua
M
Murdande
Sharad
S
Doran
Shawn D
SD
Houser
Janet A
JA
Song
Wei
W
Jones
Christopher J
CJ
Coffey
Steven B
SB
Buzon
Leanne
L
Minich
Martha L
ML
Dirico
Kenneth J
KJ
Tapley
Susan
S
McPherson
R Kirk
RK
Sugarman
Eliot
E
Harwood
H James
HJ
Esler
William
W
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008958:Models, Molecular; D051381:Rats; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D054852:Small Molecule Libraries; D000103:Acetyl-CoA Carboxylase