Discovery of a novel olefin derivative as a highly potent and selective acetyl-CoA carboxylase 2 inhibitor with in vivo efficacy

Nishiura, Yuji; Matsumura, Akira; Kobayashi, Naotake; Shimazaki, Atsuyuki; Sakamoto, Shingo; Kitade, Naohisa; Tonomura, Yutaka; Ino, Akira; Okuno, Takayuki

doi:10.1016/j.bmcl.2018.05.055

Cited by 12 publications

(9 citation statements)

References 25 publications

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“…However, a preliminary safety assessment showed neurological and cardiovascular side effects that were resolved by replacement of the alkyne moiety with a heteroaryl linker 211 . Building on this series, Boehringer Ingelheim Pharma and Shionogi research laboratory also identified a series of new molecules that selectively inhibited ACC2 compared with ACC1 without toxicity 212,213 . To the best of our knowledge, none of these agents has entered clinical testing.…”

Section: Pharmacological Inhibitorsmentioning

confidence: 99%

Lipogenesis inhibitors: therapeutic opportunities and challenges

Batchuluun

Pinkosky

Steinberg

2022

Nat Rev Drug Discov

175

135

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Section: Pharmacological Inhibitorsmentioning

confidence: 99%

Lipogenesis inhibitors: therapeutic opportunities and challenges

Batchuluun

Pinkosky

Steinberg

2022

Nat Rev Drug Discov

175

135

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“…Their results showed that it has good drug-like properties and suggested that the linker between the side chain and the aromatic ring was critical for the safety and efficacy of these types of compounds. 76 By optimizing a 2-azetidinyl-1,3-benzoxazole derivative, Takeda researchers developed a novel, selective ACC1 inhibitor: compound 14 ( Figure 3). They reported an IC 50 of 0.58 nM for hACC1 and an IC 50 of over 10 μM for hACC2.…”

Section: Inhibitors and Cytotoxic Effectsmentioning

confidence: 99%

“…After a series of optimizations and previous studies, the researchers of Shionogi & Co. developed a benzothiazole derivative with high activity and selectivity for ACC2: compound 13 (Figure 3). Their results showed that it has good drug‐like properties and suggested that the linker between the side chain and the aromatic ring was critical for the safety and efficacy of these types of compounds 76 …”

Section: Lipogenic Enzymes’ Inhibitorsmentioning

confidence: 99%

Inhibitors of lipogenic enzymes as a potential therapy against cancer

et al. 2020

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Cancer cells rely on several metabolic pathways such as lipid metabolism to meet the increase in energy demand, cell division, and growth and successfully adapt to challenging environments. Fatty acid synthesis is therefore commonly enhanced in many cancer cell lines. Thus, relevant efforts are being made by the scientific community to inhibit the enzymes involved in lipid metabolism to disrupt cancer cell proliferation. We review the rapidly expanding body of inhibitors that target lipid metabolism, their side effects, and current status in clinical trials as potential therapeutic approaches against cancer. We focus on their molecular, biochemical and structural properties, selectivity and effectiveness and discuss their potential role as antitumor drugs.

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“…We have recently discovered compound 2e (Fig. 1), a novel olefin derivative, as a potent ACC2-selective inhibitor, with IC 50 values of 1.9 and 1950 nM for ACC2 and ACC1, respectively (Nishiura et al, 2018). In the present study, we evaluated a safety profile of compound 2e in healthy rats and examined its ACC2-dependent or -independent metabolic effects with db/db mice and ACC2 knockout mice.…”

Section: Introductionmentioning

confidence: 92%

“…Compound 2e and A-908292 were synthesized at the Shionogi Pharmaceutical Research Center (Osaka, Japan) according to the procedures described in previous reports (Gu et al, 2006;Nishiura et al, 2018). For toxicological study, compound 2e was dissolved in vehicle consisting of polyethylene glycol 400/Tween 80 (95:5 by volume).…”

Section: Test Compoundsmentioning

confidence: 99%

A Novel Acetyl-CoA Carboxylase 2 Selective Inhibitor Improves Whole-Body Insulin Resistance and Hyperglycemia in Diabetic Mice through Target-Dependent Pathways

Takagi

Tanimoto

Shimazaki

et al. 2020

J Pharmacol Exp Ther

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Excess intramyocellular lipid (IMCL) deposition in skeletal muscle is closely associated with insulin resistance. Pharmacological inhibition of acetyl-CoA carboxylase (ACC) 2 offers a promising approach to treat insulin resistance through stimulation of mitochondrial fatty acid oxidation (FAO) and reduction of IMCL deposition. Previously reported experimental ACC2 inhibitors exhibited plasma glucose-lowering effects in diabetic rodents. However, their antidiabetic action may be potentially biased by off-target effects on triglyceride metabolism or by neurologic side effects. In this study, we investigated a safety profile, target dependency of its action, and antidiabetic efficacy of compound 2e, a novel olefin derivative potent ACC2 selective inhibitor. Four-day administration of suprapharmacological dose of compound 2e did not exhibit any obvious side effects in Sprague-Dawley rats. In db/db mice, single administration of compound 2e led to significantly elevated FAO and reduced IMCL deposition in skeletal muscle. In ACC2 knockout mice, treatment with pharmacological doses of compound 2e did not reduce plasma triglyceride levels, whereas A-908292, a previously reported ACC2 inhibitor, caused a significant triglyceride reduction, showing that compound 2e was devoid of off-target triglyceride-lowering activity. Chronic treatment of db/db mice with compound 2e improved hyperglycemia but did not decrease plasma triglyceride levels. Additionally, compound 2e showed significant improvements of whole-body insulin resistance in the clamp study and insulin tolerance test. Collectively, compound 2e demonstrated a good safety profile and significant antidiabetic effects through inhibition of ACC2-dependent pathways. These findings provide further evidence that selective inhibition of ACC2 is an attractive strategy against insulin resistance and type 2 diabetes. SIGNIFICANCE STATEMENTThis study shows that pharmacological inhibition of acetyl-CoA carboxylase (ACC) 2 leads to significant improvements in wholebody glucose homeostasis, independently of off-target metabolic pathways and toxicity, which were observed in previously reported ACC2 inhibitors. These findings support the concept that ACC2-selective inhibitors will be a novel remedy for treatment of type 2 diabetes.

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Discovery of a novel olefin derivative as a highly potent and selective acetyl-CoA carboxylase 2 inhibitor with in vivo efficacy

Cited by 12 publications

References 25 publications

Lipogenesis inhibitors: therapeutic opportunities and challenges

Lipogenesis inhibitors: therapeutic opportunities and challenges

Inhibitors of lipogenic enzymes as a potential therapy against cancer

A Novel Acetyl-CoA Carboxylase 2 Selective Inhibitor Improves Whole-Body Insulin Resistance and Hyperglycemia in Diabetic Mice through Target-Dependent Pathways

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