Design, synthesis, and structure–activity relationships of spirolactones bearing 2-ureidobenzothiophene as acetyl-CoA carboxylases inhibitors

Yamashita, Tohru; Endo, Satoshi; Yamamoto, Makoto; Kakegawa, Keiko; Watanabe, Hiroyuki; Miwa, Katsuhiko; Yamano, Toru; Funata, Masaaki; Sakamoto, Jyun-Ichi; Tani, Akiko; Mol, Clifford D.; Zou, Hua; Dougan, D.R.; Sang, Bi‐Ching; Snell, G.; Fukatsu, K.

doi:10.1016/j.bmcl.2011.08.117

Cited by 16 publications

(7 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…36,37 Compound 4 has been shown crystalographically to bind to the CT domain of ACC ( Figure 3). 8 Modeling of 4 with hACC2 suggests that the two amide carbonyl oxygens make key interactions with ACC, the morpholine amide with Gly 2162 and the anthracene amide with Glu 2230 .…”

Section: ■ In Vivo Pharmacologymentioning

confidence: 98%

“…Takeda’s work to develop ACC inhibitors was initiated by the examination of a known inhibitor 4 published by Pfizer ( 4 , hACC2 IC 50 = 34 nM, hACC1 IC 50 = 550 nM) (Figure ). , Compound 4 has been shown crystalographically to bind to the CT domain of ACC (Figure ) . Modeling of 4 with hACC2 suggests that the two amide carbonyl oxygens make key interactions with ACC, the morpholine amide with Gly 2162 and the anthracene amide with Glu 2230 .…”

Section: In Vivo Pharmacologymentioning

confidence: 99%

See 1 more Smart Citation

Recent Advances in the Development of Acetyl-CoA Carboxylase (ACC) Inhibitors for the Treatment of Metabolic Disease

Bourbeau

Bartberger

2014

J. Med. Chem.

View full text Add to dashboard Cite

The development of acetyl-CoA carboxylase (ACC) inhibitors for the treatment of metabolic disease has been pursued by the pharmaceutical industry for some time. A number of recent disclosures describing potent ACC inhibitors have been reported by multiple research groups. Unlike many prior publications in this area, more recent publications contain a significant amount of in vivo efficacy data generated by long-term experiments in rodent models of metabolic disease. Additionally, one compound has been advanced to human clinical studies. The results from these studies should allow researchers to better gauge the potential utility of ACC inhibition for the treatment of human disease.

show abstract

Section: ■ In Vivo Pharmacologymentioning

confidence: 98%

Section: In Vivo Pharmacologymentioning

confidence: 99%

Recent Advances in the Development of Acetyl-CoA Carboxylase (ACC) Inhibitors for the Treatment of Metabolic Disease

Bourbeau

Bartberger

2014

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…The crystal structure of human ACC2 CT domain enabled identification of amino acids responsible for inhibitor binding and elucidated the role of extended C-terminus specific for human (metazoan) enzyme in stabilization of CT dimer interface and inhibitor binding region (Madauss et al, 2009). A series of modified CP-640186 derivatives designed on the basis of these structural data led to the discovery of novel human ACCase inhibitor named 26h (spirolactones bearing 2-ureidobenzothiophene) of improved activity, which discriminated between ACC1 and ACC2 enzymes (Yamashita et al, 2011).…”

Section: Human Accase As Target In Diseases Treatmentmentioning

confidence: 99%

OPINIONS Acetyl-coenzyme A carboxylase – an attractive enzyme for biotechnology

Podkowiński¹,

Tworak²

2011

bta

View full text Add to dashboard Cite

Acetyl-CoA carboxylase catalyzes the carboxylation of acetyl-CoA to malonyl-CoA. This reaction constitutes the first committed step of fatty acid synthesis in most organisms, while its product also serves as a universal precursor for various other high-value compounds. The important regulatory and rate-limiting role of acetyl-CoA carboxylase makes this enzyme a powerful tool in a variety of biotechnological and medical projects. This review presents the current knowledge on structural and functional features of the enzyme and focuses on its divergent applications. Different metabolic engineering attempts that lead to the production of various compounds, such as fatty acids, polyketides or flavonoids, are presented and their advantages and limitations discussed. The importance of studies on acetyl-CoA carboxylase activity for design and development of new herbicides and antibiotics as well as for medical intervention is also highlighted. Acetyl-coenzyme A carboxylase -enzyme architecture, biochemistry and its role in cell physiologyA variety of biotechnological projects targeted to modulate acetyl-coenzyme A carboxylase activity in bacteria, plants and humans have been proposed and experimentally tested. Here, we would like to present a comprehensive review of these strategies together with a survey of the potential of acetyl-CoA carboxylase for biotechnology.Acetyl-coenzyme A carboxylase (ACC, E.C.6.4.1.2), recognized as an essential enzyme for all Eukaryotes and the majority of Bacteria, is responsible for carboxylation of acetyl-CoA that results in malonyl-coenzyme A formation (Fig. 1). Malonyl-CoA is a major building block for compounds such as fatty acids, polyketides and flavonoids -important components for cell growth, as well as for food, pharmaceuticals and energy production.The malonyl-CoA synthesis consists of two half-reactions (Nikolau et al., 2003). The first one, adenosine triphosphate-dependent carboxylation of biotin prosthetic group covalently bound to a module named biotin carboxyl carrier protein (BCCP), is catalyzed by ACCase segment of biotin carboxylase activity (BC) (Fig. 2). This reaction is immediately followed by the second half-re action: the transfer of a carboxyl group from carboxylated biotin to acetyl-CoA, resulting in malonyl-CoA formation. Carboxyl transferase (CT) is a module that catalyzes the second reaction and provides the required specificity in recognition of the carboxyl acceptor (acetyl-CoA). The ACCase model usually presents BCCP, a module with covalently attached biotin, as a beam responsible for biotin dislocation between two active centers -one with BT and the other with CT activity. The three (Fig. 3). The prokaryotic and eukaryotic types of ACCases are evolutionary related and the phylogeny of the modules provides some hints about their cenancestor, a split between Archaea and Bacteria, and arising of Eukaryota (Lombard and Moreira, 2011).Phylogeny is out of scope of this manuscript, but acetyl-coenzyme A carboxylases from various organisms representing v...

show abstract

“…Driven largely by the initial ACC2 knockout data published by Wakil, there have been significant efforts targeting ACC inhibition as a treatment for metabolic syndrome. − Our own work in this area began with a high-throughput screening (HTS) campaign initially targeting human ACC2 (hACC2), with follow-up counter screening against human ACC1 (hACC1). Our screening campaign identified biphenyl oxadiazole 1 as a starting point for further investigation (hACC2 IC 50 = 841 nM, hACC1 IC 50 = 4280 nM).…”

Section: Introductionmentioning

confidence: 99%

Piperazine Oxadiazole Inhibitors of Acetyl-CoA Carboxylase

et al. 2013

View full text Add to dashboard Cite

Acetyl-CoA carboxylase (ACC) is a target of interest for the treatment of metabolic syndrome. Starting from a biphenyloxadiazole screening hit, a series of piperazine oxadiazole ACC inhibitors was developed. Initial pharmacokinetic liabilities of the piperazine oxadiazoles were overcome by blocking predicted sites of metabolism, resulting in compounds with suitable properties for further in vivo studies. Compound 26 was shown to inhibit malonyl-CoA production in an in vivo pharmacodynamic assay and was advanced to a long-term efficacy study. Prolonged dosing with compound 26 resulted in impaired glucose tolerance in diet-induced obese (DIO) C57BL6 mice, an unexpected finding.

show abstract

Design, synthesis, and structure–activity relationships of spirolactones bearing 2-ureidobenzothiophene as acetyl-CoA carboxylases inhibitors

Cited by 16 publications

References 11 publications

Recent Advances in the Development of Acetyl-CoA Carboxylase (ACC) Inhibitors for the Treatment of Metabolic Disease

Recent Advances in the Development of Acetyl-CoA Carboxylase (ACC) Inhibitors for the Treatment of Metabolic Disease

OPINIONS Acetyl-coenzyme A carboxylase – an attractive enzyme for biotechnology

Piperazine Oxadiazole Inhibitors of Acetyl-CoA Carboxylase

Contact Info

Product

Resources

About