The synthesis and structure-activity relationship studies of selective acetyl-CoA carboxylase inhibitors containing 4-(thiazol-5-yl)but-3-yn-2-amino motif: polar region modifications.
The structure-activity relationship study focused on the polar region of the HTS hit A-80040 (1) producing several series of potent and selective ACC2 inhibitors. The SAR suggests a compact lipophilic pocket that does not tolerate polar and ionic groups. Replacement of the hydroxyurea group with isoxazoles improves ACC2 selectivity while maintaining potency. Variations at the propargylic site of 11a reduce ACC2 potency.
Xu
Xiangdong
X
Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. xiangdong.xu@abbott.com
Weitzberg
Moshe
M
Keyes
Robert F
RF
Li
Qun
Q
Wang
Rongqi
R
Wang
Xiaojun
X
Zhang
Xiaolin
X
Frevert
Ernst U
EU
Camp
Heidi S
HS
Beutel
Bruce A
BA
Sham
Hing L
HL
Gu
Yu Gui
YG
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000235:genetics; D000480:Alkynes / Q000138:chemical synthesis* / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D006918:Hydroxyurea / Q000737:chemistry; D007555:Isoxazoles / Q000138:chemical synthesis / Q000494:pharmacology; D008968:Molecular Conformation; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
D000480:Alkynes; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D011994:Recombinant Proteins; D013844:Thiazoles; D000103:Acetyl-CoA Carboxylase; D006918:Hydroxyurea