- Structural development studies of pyrazoloketone-derived acetyl-CoA carboxylase inhibitors
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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.
- Okazaki, Shogo,Sakai, Taki,Ishikawa, Minoru,Hashimoto, Yuichi,Yamaguchi, Takao
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p. 595 - 607
(2019/05/21)
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- Benzimidazolone p38 inhibitors
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The synthesis and in vitro p38α activity of a novel series of benzimidazolone inhibitors is described. The p38α SAR is consistent with a mode of binding wherein the benzimidazolone carbonyl serves as the H-bond acceptor to Met109 of p38α in a manner analogous to the pyridine nitrogen of prototypical pyridylimidazole p38 inhibitors. Potent p38α activity comparable to that of several previously reported p38 inhibitors is observed for this novel chemotype.
- Dombroski, Mark A.,Letavic, Michael A.,McClure, Kim F.,Barberia, John T.,Carty, Thomas J.,Cortina, Santo R.,Csiki, Csilla,Dipesa, Alan J.,Elliott, Nancy C.,Gabel, Christopher A.,Jordan, Crystal K.,Labasi, Jeff M.,Martin, William H.,Peese, Kevin M.,Stock, Ingrid A.,Svensson, Linne,Sweeney, Francis J.,Yu, Chul H.
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p. 919 - 923
(2007/10/03)
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