Discovery of PEGylated 6-Benzhydryl-4-amino-quinazolines as Peripherally Restricted CB1R Inverse Agonists

This is the authors' abstract. We don't add key points for this paper.

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.