TY - JOUR
T1 - Structural development studies of pyrazoloketone-derived acetyl-CoA carboxylase inhibitors
AU - Okazaki, Shogo
AU - Sakai, Taki
AU - Ishikawa, Minoru
AU - Hashimoto, Yuichi
AU - Yamaguchi, Takao
N1 - Funding Information:
The work described in this paper was partially supported by Grants-in-Aid for Scientific Research (KAKENHI, Grant-in-Aid for Young Scientists (B), No. 26810091 and 16K17930 to T.Y.) from The Ministry of Education, Culture, Sports, Science and Technology in Japan (MEXT), and the Japan Society for the Promotion of Science (JSPS), and Platform for Drug Discovery, Informatics, and Structural Life Science.
Publisher Copyright:
© 2017 The Japan Institute of Heterocyclic Chemistry.
PY - 2017
Y1 - 2017
N2 - Acetyl-CoA carboxylase (ACC) plays a key role in fatty acid homeostasis in humans, and inhibitors of ACC are expected to inhibit fatty acid biosynthesis and to activate fatty acid β-oxidation. Therefore, they are considered to be candidates for treatment of metabolic syndrome and related diseases. In this context, an upstream kinase of ACC, adenosine monophosphate-activated protein kinase (AMPK), has also recently emerged as a potential therapeutic target, because it phosphorylates and inactivates ACC. Here, we designed a fused molecule consisting of a pyrazoloketone-type ACC inhibitor and a recently discovered AMPK activator, aiming to develop a novel combined ACC inhibitor/AMPK activator to regulate fatty acid levels. The designed compound was prepared through a convergent synthetic route. This compound and its methyl ester analogue showed potent ACC2-inhibitory activity with IC50 values of 8.8 and 1.3 μM, respectively. Exomethylene derivatives, obtained from an unexpected side reaction during deprotection, also exhibited ACC2-inhibitory activity.
AB - Acetyl-CoA carboxylase (ACC) plays a key role in fatty acid homeostasis in humans, and inhibitors of ACC are expected to inhibit fatty acid biosynthesis and to activate fatty acid β-oxidation. Therefore, they are considered to be candidates for treatment of metabolic syndrome and related diseases. In this context, an upstream kinase of ACC, adenosine monophosphate-activated protein kinase (AMPK), has also recently emerged as a potential therapeutic target, because it phosphorylates and inactivates ACC. Here, we designed a fused molecule consisting of a pyrazoloketone-type ACC inhibitor and a recently discovered AMPK activator, aiming to develop a novel combined ACC inhibitor/AMPK activator to regulate fatty acid levels. The designed compound was prepared through a convergent synthetic route. This compound and its methyl ester analogue showed potent ACC2-inhibitory activity with IC50 values of 8.8 and 1.3 μM, respectively. Exomethylene derivatives, obtained from an unexpected side reaction during deprotection, also exhibited ACC2-inhibitory activity.
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U2 - 10.3987/COM-16-S(S)30
DO - 10.3987/COM-16-S(S)30
M3 - Article
AN - SCOPUS:85065611075
VL - 95
SP - 595
EP - 607
JO - Heterocycles
JF - Heterocycles
SN - 0385-5414
IS - 1
ER -