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Last update 08 May 2025

RXFP4

Last update 08 May 2025

Basic Info

Synonyms

G protein-coupled receptor 100, G-protein coupled receptor 100, G-protein coupled receptor GPCR142

+ [12]

Introduction

High affinity receptor for INSL5. Also acts as a receptor for RLN3/relaxin-3, as well as bradykinin and kallidin. Binding of the ligand inhibit cAMP accumulation.

Drugs associated with RXFP4

JK0621-D008

Target

RXFP4

Mechanism

RXFP4 agonists

Active Org.-

Originator Org.

Shanghai Institute of Materia Medica Chinese Academy of Sci

Active Indication-

Inactive Indication

Obesity

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with RXFP4

100 Translational Medicine associated with RXFP4

0 Patents (Medical) associated with RXFP4

Literatures (Medical) associated with RXFP4

01 Jul 2025·Biochemical Pharmacology

Relief of loperamide-induced constipation by peptidic and small molecule RXFP4 agonists in mice

Article

Author: Chen, Yan ; Yan, Shiyu ; Wang, Jiang ; Liu, Hong ; Wang, Qiuying ; Zhou, Qingtong ; Wang, Ming-Wei ; Yang, Dehua

Constipation is a common gastrointestinal disorder often treated symptomatically as the existing therapies all have significant side-effects. The relaxin/insulin-like family peptide receptor 4 (RXFP4), a class A G protein-coupled receptor, has emerged as a potential drug target for this indication as it regulates intestinal motility. Here, we investigated the therapeutic effects of both peptidic (insulin-like peptide 5, INSL5) and small molecule (DC591053) RXFP4 agonists on loperamide-induced constipation in mice. Fecal water content, fecal weight, colonic transit time, and serum levels of neurotransmitters such as nitric oxide (NO), serotonin (5-HT), and vasoactive intestinal peptide (VIP) were assessed, in conjunction with the examination of colon tissue histology and expression levels of aquaporin 3 (AQP3), transient receptor potential vanilloid 1 (TRPV1), and calcitonin gene-related peptide (CGRP). It was found that both INSL5 and DC591053 dose-dependently increased fecal water content and weight, accelerated colonic transit, and improved colon morphology in constipated mice, accompanied by the altered expression levels of factors related to constipation. Comparative analysis revealed that while the two agonists produced similar beneficial outcomes, their different chemical nature may affect pharmacokinetics property and receptor engagement. Our results suggest that the activation of RXFP4 presents a novel approach to alleviating constipation.

10 Apr 2025·Journal of Medicinal Chemistry

Development of Diphenyl-1,2,4-Oxadiazole Analogues as Allosteric Modulators of the RXFP3 Receptor: Evaluation of Importance of the N-Substituted-2-Pyrrolidone Moiety in RLX-33

Article

Author: Bender, Brooke N. ; Kerr, Andrew T. ; Guan, Dongliang ; Barrus, Daniel G. ; Gay, Elaine A. ; Chaminda Lakmal, Hetti Handi ; Rahman, Md Toufiqur ; Jin, Chunyang ; Besheer, Joyce ; Mosera, Alejandro M.

Relaxin-3/RXFP3 antagonism is a novel strategy for drug development to treat alcohol use disorder (AUD). We recently discovered the first-in-class RXFP3 negative allosteric modulators (NAMs), represented by RLX-33, which significantly reduced alcohol consumption in rats. In this study, we report the design and synthesis of a series of diphenyl-1,2,4-oxadiazole analogues derived from RLX-33. Structure-activity relationship studies of sites A and B of RLX-33 revealed that the aromatic ring at site A is not required for RXFP3 allosteric modulation and the pyrrolidone linker at site B could be replaced with a cyclic or linear alkylamine. Compound (R,R)-3 has improved potency and ADME properties (e.g., solubility and metabolic stability) compared to RLX-33, while maintaining high receptor subtype selectivity over RXFP1 and RXFP4. Importantly, (R,R)-3 significantly attenuated alcohol self-administration without affecting sucrose self-administration and general locomotor activity in rats, demonstrating the potential of RXFP3 NAMs as promising drug candidates for AUD.

12 Dec 2024·Journal of Medicinal Chemistry

Engineering of Novel Analogues That Are More Receptor-Selective and Potent than the Native Hormone, Insulin-like Peptide 5 (INSL5)

Article

Author: Handley, Thomas N. G. ; Bathgate, Ross A. D. ; Chalmers, David K. ; Wu, Hongkang ; Rosengren, K. Johan ; Hartono, Herodion A. ; Hossain, Mohammed Akhter ; Hoare, Bradley L.

Insulin-like peptide 5 (INSL5) targets the G protein-coupled receptor, relaxin family peptide receptor 4 (RXFP4), predominantly coexpressed in the colorectum. While INSL5 also binds to the related receptor RXFP3, it does not activate it. The INSL5/RXFP4 axis is a promising target for treating gastrointestinal disorders such as constipation. Despite its therapeutic potential, the clinical application of INSL5 has been hindered by synthesis complexities, necessitating the need for more accessible yet potent mimetics. In this study, we engineered an INSL5 analogue A13:B7-24-GG, featuring a simplified two-chain, two-disulfide scaffold with 32 amino acids, as opposed to the 45 amino acids found in native INSL5 (two-chain, three-disulfide), improving the synthesis yield by 19.5-fold. Additionally, A13:B7-24-GG demonstrates ∼4-fold higher potency (EC₅₀ = 1.17 nM vs 4.57 nM) and ∼11 times greater selectivity than native INSL5, with significantly reduced RXFP3 binding affinity, positioning it as a promising new therapeutic candidate for the treatment of constipation.

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RXFP4

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