Discovery of novel (4-piperidinyl)-piperazines as potent and orally active acetyl-CoA carboxylase 1/2 non-selective inhibitors: F-Boc and triF-Boc groups are acid-stable bioisosteres for the Boc group

Chonan, Tomomichi; Wakasugi, Daisuke; Yamamoto, Daisuke; Yashiro, Miyoko; Oi, Takahiro; Tanaka, Hiroki; Ohoka-Sugita, Ayumi; Io, Fusayo; Koretsune, Hiroko; Hiratate, Akira

doi:10.1016/j.bmc.2011.01.041

Cited by 32 publications

(21 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A data set of 100 (4-piperidinyl)-piperazine derivatives were collected from the literatures 2011). Chemical structures and activity data are shown in Table S1 osiris property explorer.…”

Section: Datasetmentioning

confidence: 99%

Molecular modeling study for the design of novel acetyl-CoA carboxylase inhibitors using 3D QSAR, molecular docking and dynamic simulations

Vyas

Dabasia

Qureshi

et al. 2016

Journal of Biomolecular Structure and Dynamics

View full text Add to dashboard Cite

Acetyl-CoA carboxylase (ACC) enzyme plays an important role in the regulation of biosynthesis and oxidation of fatty acids. ACC is a recognized drug target for the treatment of obesity and diabetes. Combination of ligand and structure-based in silico methods along with activity and toxicity prediction provides best lead compounds in the drug discovery process. In this study, a data-set of 100 ACC inhibitors were used for the development of comparative molecular field analysis (CoMFA) and comparative molecular similarity index matrix analysis (CoMSIA) models. The generated contour maps were used for the design of novel ACC inhibitors. CoMFA and CoMSIA models were used for the predication of activity of designed compounds. In silico toxicity risk prediction study was carried out for the designed compounds. Molecular docking and dynamic simulations studies were performed to know the binding mode of designed compounds with the ACC enzyme. The designed compounds showed interactions with key amino acid residues important for catalysis, and good correlation was observed between binding free energy and inhibition of ACC.

show abstract

“…A data set of 100 (4-piperidinyl)-piperazine derivatives were collected from the literatures 2011). Chemical structures and activity data are shown in Table S1 osiris property explorer.…”

Section: Datasetmentioning

confidence: 99%

Molecular modeling study for the design of novel acetyl-CoA carboxylase inhibitors using 3D QSAR, molecular docking and dynamic simulations

Vyas

Dabasia

Qureshi

et al. 2016

Journal of Biomolecular Structure and Dynamics

View full text Add to dashboard Cite

show abstract

“…After stirring at room temperature for 30 min, the mixture was filtered through a pad of Celite and concentrated under reduced pressure. A mixture of the residue, TPAP (22.5 (20). To an ice cold stirred solution of 19 (185 mg, 0.47 mmol) in THF (3 mL) was added MeMgBr (1.0 M THF solution, 0.94 mL, 0.94 mmol).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…Recently, it has been reported that ACC1 is overexpressed in human cancer cells, such as colon, prostate, kidney, spleen, uterine cervix, uterus body, ovary, and small intestine cancer cells and is likely involved in tumor development and progression. Thus, ACC1 is a potential target for developing novel agents as cancer therapeutics. − However, selective ACC1 inhibitors have not been reported even though there are many reports for dual ACC1/2 inhibitors − and selective ACC2 inhibitors. − For evaluation of its potential in cancer therapy, a selective ACC1 inhibitor is required. Therefore, we initiated an investigation into the generation of potent and selective ACC1 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Selective Acetyl-CoA Carboxylase (ACC) 1 Inhibitors

et al. 2018

View full text Add to dashboard Cite

We initiated our structure-activity relationship (SAR) studies for selective ACC1 inhibitors from 1a as a lead compound. SAR studies of bicyclic scaffolds revealed many potent and selective ACC1 inhibitors represented by 1f; however most of them had physicochemical issues, particularly low aqueous solubility and potent CYP inhibition. To address these two issues and improve the druglikeness of this chemical series, we converted the bicyclic scaffold into a monocyclic framework. Ultimately, this lead us to discover a novel monocyclic derivative 1q as a selective ACC1 inhibitor, which showed highly potent and selective ACC1 inhibition as well as acceptable solubility and CYP inhibition profiles. Since compound 1q displayed favorable bioavailability in mouse cassette dosing testing, we conducted in vivo PD studies of this compound. Oral administration of 1q significantly reduced the concentration of malonyl-CoA in HCT-116 xenograft tumors at doses of more than 30 mg/kg. Accordingly, our novel series of selective ACC1 inhibitors represents a set of useful orally available research tools, as well as potential therapeutic agents for cancer and fatty acid related diseases.

show abstract

“…Benzothiophene is a predominant structural core compound in drugs and device materials. − In particular, 2-aminobenzothiophenes show various biological activities, such as acetyl-CoA carboxylase inhibitor, tubulin polymerization, and mycobacterium inhibition . They are also precursors for the synthesis of the well-known drug raloxifene and its analogues .…”

Section: Introductionmentioning

confidence: 99%

Chemoselective Ullmann Reaction of α-Trisubstituted Thioamides: Synthesis of Novel 2-Iminobenzothiolanes

et al. 2021

View full text Add to dashboard Cite

New classes of unexplored benzo [b]thiolanes are synthesized from trisubstituted thioamides through coppercatalyzed intramolecular S-arylation of thioamides for the first time. This method provides good to excellent yields with fully controlled chemoselectivity. Unusually, iminobenzo[b]thiolanes are very stable under mild acidic conditions. A plausible mechanism is proposed for the chemoselective S-arylation process.

show abstract

Discovery of novel (4-piperidinyl)-piperazines as potent and orally active acetyl-CoA carboxylase 1/2 non-selective inhibitors: F-Boc and triF-Boc groups are acid-stable bioisosteres for the Boc group

Cited by 32 publications

References 21 publications

Molecular modeling study for the design of novel acetyl-CoA carboxylase inhibitors using 3D QSAR, molecular docking and dynamic simulations

Molecular modeling study for the design of novel acetyl-CoA carboxylase inhibitors using 3D QSAR, molecular docking and dynamic simulations

Discovery of Novel Selective Acetyl-CoA Carboxylase (ACC) 1 Inhibitors

Chemoselective Ullmann Reaction of α-Trisubstituted Thioamides: Synthesis of Novel 2-Iminobenzothiolanes

Contact Info

Product

Resources

About