Work

Structural Alterations of the “Address” Moiety of NAN Leading to the Discovery of a Novel Opioid Receptor Modulator with Reduced hERG Toxicity

Year: 2022

Type: article

Abstract: The search for selective opioid ligands with desired pharmacological potency and improved safety profile has always been an area of interest. Our previous effort yielded a potent opioid modulator, NAN, a 6α- N -7′-indolyl-substituted naltrexamine derivative, which exhibited promising pharmacological activities both in vitro and in vivo. However, significant human ether-a-go-go-related gene (hERG) liability limited its further development. Therefore, a systematic structural modification on NAN was conducted in order to alleviate hERG toxicity while preserving pharmacological properties, which led to the discovery of 2′-methylindolyl derivative compound 21 . Compared to NAN, compound 21 manifested overall improved pharmacological profiles. Follow-up hERG channel inhibition evaluation revealed a seven-fold decreased potency of compound 21 compared to NAN. Furthermore, several fundamental drug-like property evaluations suggested a reasonable ADME profile of 21 . Collectively, compound 21 appeared to be a promising opioid modulator for further development as a novel therapeutic agent toward opioid use disorder treatments.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.2c01499