# APJ receptor agonism for metabolic syndrome

> **NIH NIH R01** · RESEARCH TRIANGLE INSTITUTE · 2021 · $486,222

## Abstract

The overall goal of this project is to develop apelin (APJ) receptor agonists to treat diet-induced obesity
(DIO) and related metabolic syndrome. Metabolic syndrome can lead to several life threatening conditions
including hypertension, heart disease, type II diabetes, steatohepatitis, stroke, and certain types of cancer.
Available medications to treat obesity have serious side effects and limited efficacy. Thus, new medications
around novel targets are needed. The APJ receptor is a G-protein coupled receptor (GPCR) protein that is
activated by apelin peptides and a newly described hormone called TODDLER/ELABELA. It is an emerging
multi-modal target for metabolic syndrome that needs pharmacological validation. Apelin is an insulin
sensitizer that promotes fatty acid oxidation. Apelin knockout (ko) mice have higher insulin levels and glucose
intolerance along with increased abdominal fat and higher bodyweight. Apelin through its interaction with APJ
can inhibit maturation of pre-adipocytes and lipolysis in mature adipocytes. Activation of APJ by apelin in the
endothelium leads to the formation of large, non-leaky lymphatic and blood vessels that restrict the transport
of FA and their uptake in adipose. In agreement with these data, apelin ko mice have vessels that are more
amenable to FA transport. Another report has indicated that apelin transgenic mice are resistant to DIO by
virtue of increased vascular mass and mitochondrial biogenesis in skeletal muscles. Non-peptide probes of this
receptor suitable for in vivo work are not available. We have identified a structurally novel agonist scaffold for
further development through high-throughput screening. We propose to refine our early lead compounds to
produce in vivo probes of APJ using three iterative specific aims. Through aim 1, synthesis and refinement of
APJ probes will continue using medicinal chemistry approaches. Through aim 2, these compounds will be
characterized using functional and radioligand displacement assays for APJ. Potent compounds will be then
characterized using a battery of ADMET and pharmacokinetic assays. Through aim 3, in vivo testing of the best
compounds will be performed in a chronic model of DIO in rodents. Completion of the project will
pharmacologically validate APJ as a target for medications development to treat metabolic syndrome and
produce advanced lead compounds for eventual clinical development.

## Key facts

- **NIH application ID:** 10107802
- **Project number:** 5R01DK103625-05
- **Recipient organization:** RESEARCH TRIANGLE INSTITUTE
- **Principal Investigator:** RANGAN MAITRA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $486,222
- **Award type:** 5
- **Project period:** 2017-04-01 → 2024-10-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107802

## Citation

> US National Institutes of Health, RePORTER application 10107802, APJ receptor agonism for metabolic syndrome (5R01DK103625-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10107802. Licensed CC0.

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