| Autor: |
Yue-Mei, Zhang, Michael, Greco, Tonya, Le Blanc, Wensheng, Lang, Jack, Kauffman, John, Masucci, William V, Murray, Keith, Demarest, Mark Joseph, Macielag |
| Rok vydání: |
2020 |
| Zdroj: |
ACS Med Chem Lett |
| ISSN: |
1948-5875 |
| Popis: |
[Image: see text] The 6-benzhydryl-4-amino-quinolin-2-ones are peripherally restricted CB(1) receptor inverse agonists (CB(1)RIAs) that have been reported to attenuate obesity and improve insulin sensitivity in the diet-induced obese (DIO) mouse model. However, chronic dosing of select compounds from the series showed time-dependent brain accumulation despite a low brain/plasma exposure ratio. To address this issue, a PEGylation approach was employed to identify a novel series of homodimeric 6-benzhydryl-4-amino-quinazoline–PEG conjugates with an extended half-life. The lead compound 18 engaged peripheral CB(1)Rs in a gastrointestinal (GI) tract motility study and demonstrated a high level of peripheral restriction in a chronic DIO mouse pharmacokinetic study. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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