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

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.