Discovery and Characterization of the First Nonpeptide Antagonists for the Relaxin-3/RXFP3 System

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2022 May 20

PMID 35594150

Authors

Elaine A Gay

Dongliang Guan

Kalynn Van Voorhies

Vineetha Vasukuttan

Kelly M Mathews

Joyce Besheer

Chunyang Jin

Affiliations

Soon will be listed here.

Abstract

The neuropeptide relaxin-3/RXFP3 system is involved in many important physiological processes such as stress responses, appetite control, and motivation for reward. To date, pharmacological studies of RXFP3 have been limited to peptide ligands. In this study, we report the discovery of the first small-molecule antagonists of RXFP3 through a high-throughput screening campaign. Focused structure-activity relationship studies of the hit compound resulted in RLX-33 () that was able to inhibit relaxin-3 activity in a battery of functional assays. RLX-33 is selective for RXFP3 over RXFP1 and RXFP4, two related members in the relaxin/insulin superfamily, and has favorable pharmacokinetic properties for behavioral assessment. When administered to rats intraperitoneally, RLX-33 blocked food intake induced by the RXFP3-selective agonist R3/I5. Collectively, our findings demonstrated that RLX-33 represents a promising antagonist scaffold for the development of drugs targeting the relaxin-3/RXFP3 system.

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