Research Article Details
| Article ID: | A13288 |
| PMID: | 30049586 |
| Source: | Bioorg Med Chem |
| Title: | Design, synthesis and biological evaluation of novel spiro-pentacylamides as acetyl-CoA carboxylase inhibitors. |
| Abstract: | Acetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in de novo lipogenesis and plays an important role in the regulation of fatty acid oxidation. Therefore, ACC inhibition offers a promising option for intervention in nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2DM) and cancer. In this paper, a series of spiropentacylamide derivatives were synthesized and evaluated for their ACC1/2 inhibitory activities and anti-proliferation effects on A549, H1975, HCT116, SW620 and Caco-2 cell lines in vitro. Compound 6o displayed potent ACC1/2 inhibitory activity (ACC1 IC50 = 0.527 μM, ACC2 IC50 = 0.397 μM) and the most potent anti-proliferation activities against A549, H1975, HCT116, SW620 and Caco-2 cell lines, with IC50 values of 1.92 μM, 0.38 μM, 1.22 μM, 2.05 μM and 5.42 μM respectively. Further molecular docking studies revealed that compound 6o maintained hydrogen bonds between the two carbonyls and protein backbone NHs (Glu-B2026 and Gly-B1958). These results indicate that compound 6o is a promising ACC1/2 inhibitor for the potent treatment of cancer. |
| DOI: | 10.1016/j.bmc.2018.03.014 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S07 | Anti-lipogenesis | de novo lipogenesis; de novo lipogenesis; DNL; anti-lipogenic mechanisms; adipogenesis; anti-obesity | stearoyl-CoA desaturase 1 (SCD-1); Acetyl-coenzyme carboxylase; acyl-CoA carboxylase inhibitor (ACC inhibitor); stearoyl Coenzyme A desaturase inhibitor (SCD inhibitor); THR-beta selective agonist; DGAT2 inhibitor; FASN inhibitor | Aramchol; Firsocostat (GS-0976); VK-2809; ION 224 | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |