Open AccessDiscovery of PEGylated 6-Benzhydryl-4-amino-quinazolines as Peripherally Restricted CB1R Inverse Agonists
Author(s) -
Zhang Yue-mei,
Michael N. Greco,
Tonya Le Blanc,
Wensheng Lang,
Jack A. Kauffman,
John A. Masucci,
William V. Murray,
Keith T. Demarest,
Mark J. Macielag
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00495
Subject(s) - pegylation , inverse agonist , pharmacology , pharmacokinetics , chemistry , dosing , medicine , receptor , biochemistry , antagonist , polyethylene glycol
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.