Work

Design, Synthesis, and Characterization of α-Ketoheterocycles That Additionally Target the Cytosolic Port Cys269 of Fatty Acid Amide Hydrolase

Year: 2014

Type: article

Abstract: A series of α-ketooxazoles incorporating electrophiles at the C5 position of the pyridyl ring of 2 (OL-135) and related compounds were prepared and examined as inhibitors of fatty acid amide hydrolase (FAAH) that additionally target the cytosolic port Cys269. From this series, a subset of the candidate inhibitors exhibited time-dependent FAAH inhibition and noncompetitive irreversible inactivation of the enzyme, consistent with the targeted Cys269 covalent alkylation or addition, and maintained or enhanced the intrinsic selectivity for FAAH versus other serine hydrolases. A preliminary in vivo assessment demonstrates that these inhibitors raise endogenous brain levels of anandamide and other FAAH substrates upon intraperitoneal (i.p.) administration to mice, with peak levels achieved within 1.5-3 h, and that the elevations of the signaling lipids were maintained >6 h, indicating that the inhibitors effectively reach and remain active in the brain, inhibiting FAAH for a sustained period.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/jm401820q

Authors: Katerina Otrubova, Benjamin F. Cravatt, Dale L. Boger

Institution: Scripps Research Institute

Language: English

Topic: Cannabis and Cannabinoid Research

Subfield: Pharmacology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,500