Discovery of PEGylated 6-Benzhydryl-4-amino-quinazolines as Peripherally Restricted CB1R Inverse Agonists.
ACS Med Chem Lett
; 11(12): 2504-2509, 2020 Dec 10.
Article
em En
| MEDLINE
| ID: mdl-33335674
ABSTRACT
The 6-benzhydryl-4-amino-quinolin-2-ones are peripherally restricted CB1 receptor inverse agonists (CB1RIAs) 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 CB1Rs in a gastrointestinal (GI) tract motility study and demonstrated a high level of peripheral restriction in a chronic DIO mouse pharmacokinetic study.
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01-internacional
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MEDLINE
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En
Ano de publicação:
2020
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Article