2-(4-Carbonylphenyl)benzoxazole inhibitors of CETP: Attenuation of hERG binding and improved HDLc-raising efficacy

Sweis, Ramzi F.; Hunt, Julianne A.; Sinclair, Peter J.; Chen, Ying; Eveland, Suzanne S.; Guo, Qiu; Hyland, Sheryl A.; Milot, Denise P.; Cumiskey, Anne-Marie; Latham, Melanie; Rosa, Raymond; Peterson, L.; Sparrow, Carl P.; Anderson, Matt S.

doi:10.1016/j.bmcl.2011.02.049

Cited by 11 publications

(11 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Clofilium tosylate was purchased from Sigma-Aldrich. 1 H and 13 C NMR spectra were recorded 6). To a solution of 5 (321 mg, 1 mmol) in DMF (5 mL) was added K 2 CO 3 (415 mg, 3 mmol), followed by N-ethylheptylamine (190 μL, 1 mmol).…”

Section: ■ Conclusionmentioning

confidence: 99%

“…1 H NMR (400 MHz, CDCl 3 ) δ 7.34 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 3.61 (s, 2H), 2.60 (q, J = 7.2 Hz, 2H), 2.52 (t, J = 7.6 Hz, 2H), 1.52−1.48 (m, 2H), 1.31−1.27 (m, 8H), 1.10 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H) ppm. 13 C NMR (101 MHz, CDCl 3 ) δ 133.9, 132.9, 128.5, 121.9, 85.8, 83.9, 53.6, 47. (Z)-N-Ethyl-N-(4-phenylbut-2-en-1-yl)heptan-1-amine (79).…”

Section: ■ Conclusionmentioning

confidence: 99%

“…1 H NMR (400 MHz, CDCl 3 ) δ 7.28 (d, J = 6.8 Hz, 2H), 7.18 (d, J = 7.2 Hz, 2H), 5.75−5.69 (m, 1H), 5.66−5.60 (m, 1H), 3.44 (d, J = 6.8 Hz, 2H), 3.23 (d, 6.4 Hz, 2H), 2.57 (q, J = 14.0, 6.8 Hz, 2H), 2.45 (t, J = 7.6 Hz, 2H), 1.47 (m, 2H), 1.27−1.26 (m, 8H), 1.05 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 5.6 Hz, 3H) ppm. 13 N-Ethyl-N-(4-phenylbutyl)heptan-1-amine (81). Allylamine 78 (180 mg, 0.6 mmol) and Pd/C (10% w/w Pd, 55 mg, 30 wt %) were dissolved in MeOH (10 mL).…”

Section: ■ Conclusionmentioning

confidence: 99%

See 2 more Smart Citations

Removal of Human Ether-à-go-go Related Gene (hERG) K⁺ Channel Affinity through Rigidity: A Case of Clofilium Analogues

Louvel

Carvalho

et al. 2013

J. Med. Chem.

View full text Add to dashboard Cite

Cardiotoxicity is a side effect that plagues modern drug design and is very often due to the off-target blockade of the human ether-à-go-go related gene (hERG) potassium channel. To better understand the structural determinants of this blockade, we designed and synthesized a series of 40 derivatives of clofilium, a class III antiarrhythmic agent. These were evaluated in radioligand binding and patch-clamp assays to establish structure-affinity relationships (SAR) for this potassium channel. Efforts were especially focused on studying the influence of the structural rigidity and the nature of the linkers composing the clofilium scaffold. It was shown that introducing triple bonds and oxygen atoms in the n-butyl linker of the molecule greatly reduced affinity without significantly modifying the pKa of the essential basic nitrogen. These findings could prove useful in the first stages of drug discovery as a systematic way of reducing the risk of hERG K(+) channel blockade-induced cardiotoxicity.

show abstract

Section: ■ Conclusionmentioning

confidence: 99%

Section: ■ Conclusionmentioning

confidence: 99%

Section: ■ Conclusionmentioning

confidence: 99%

See 1 more Smart Citation

Removal of Human Ether-à-go-go Related Gene (hERG) K⁺ Channel Affinity through Rigidity: A Case of Clofilium Analogues

Louvel

Carvalho

et al. 2013

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…[144] Sweis and co-workersh ave explored enantiomers 109 (IC 50 = 22 nm)a nd 110( IC 50 = 18 nm)a sp otent CETP inhibitors, as they increased the HDLc level by 33 and 27 mg dL À1 ,r espectively,i natransgenic mouse Parkinson'sd isease (PD) model ( Figure 46). [145] In the same year,t his group also explored compound 111 (IC 50 = 13 nm)a sapotent CETP inhibitor,a si t raised HDLc levelsb y2 4mgdL À1 in at ransgenic mouseP D model (Figure 46). [146] Compound 112 (Figure 46) also showedp otent CETP inhibitory activity (IC 50 = 16 nm), increased the HDLc level by 24 mg dL À1 ,a nd had ag ood pharmacokinetic profile.…”

Section: Cardiovascular Disease(cd)mentioning

confidence: 99%

Recent Advances in the Development of Pharmacologically Active Compounds that Contain a Benzoxazole Scaffold

et al. 2015

View full text Add to dashboard Cite

In recenty ears, the emergence of biologically active compounds that contain ah eterocyclic ring has gained ag reat deal of attention among medicinal chemists. Among these, benzoxazole-based compounds are particularly attractive because of their wide range of pharmacological activities. In this focus review, we highlight recent advancements in the development of benzoxazole-based pharmacologically active compounds since the year 2000.

show abstract

“…2-Aminobenzoxazoles and their N -substituted analogues play an important role in medicinal chemistry and chemical biology. − They are described as potential therapeutic agents including various enzyme inhibitors (proteases, chymase, butyrylcholinesterase, topoisomerase II inhibitors, etc. ). ,, They also have applications in materials chemistry .…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Various 2-Aminobenzoxazoles: The Study of Cyclization and Smiles Rearrangement

2019

View full text Add to dashboard Cite

This study reports two synthetic approaches leading to 2-aminobenzoxazoles and their N-substituted analogues. Our first synthetic strategy involves a reaction between various o-aminophenols and N-cyano-N-phenyl-p-toluenesulfonamide as a nonhazardous electrophilic cyanating agent in the presence of Lewis acid. The second synthetic approach uses the Smiles rearrangement upon activation of benzoxazole-2-thiol with chloroacetyl chloride. Both developed synthetic protocols are widely applicable, afford the desired aminobenzoxazoles in good to excellent yields, and use nontoxic and inexpensive starting material.

show abstract

2-(4-Carbonylphenyl)benzoxazole inhibitors of CETP: Attenuation of hERG binding and improved HDLc-raising efficacy

Cited by 11 publications

References 23 publications

Removal of Human Ether-à-go-go Related Gene (hERG) K⁺ Channel Affinity through Rigidity: A Case of Clofilium Analogues

Removal of Human Ether-à-go-go Related Gene (hERG) K⁺ Channel Affinity through Rigidity: A Case of Clofilium Analogues

Recent Advances in the Development of Pharmacologically Active Compounds that Contain a Benzoxazole Scaffold

Synthesis of Various 2-Aminobenzoxazoles: The Study of Cyclization and Smiles Rearrangement

Contact Info

Product

Resources

About

2-(4-Carbonylphenyl)benzoxazole inhibitors of CETP: Attenuation of hERG binding and improved HDLc-raising efficacy

Cited by 11 publications

References 23 publications

Removal of Human Ether-à-go-go Related Gene (hERG) K+ Channel Affinity through Rigidity: A Case of Clofilium Analogues

Removal of Human Ether-à-go-go Related Gene (hERG) K+ Channel Affinity through Rigidity: A Case of Clofilium Analogues

Recent Advances in the Development of Pharmacologically Active Compounds that Contain a Benzoxazole Scaffold

Synthesis of Various 2-Aminobenzoxazoles: The Study of Cyclization and Smiles Rearrangement

Contact Info

Product

Resources

About

Removal of Human Ether-à-go-go Related Gene (hERG) K⁺ Channel Affinity through Rigidity: A Case of Clofilium Analogues

Removal of Human Ether-à-go-go Related Gene (hERG) K⁺ Channel Affinity through Rigidity: A Case of Clofilium Analogues