Chronic inflammatory pain (CIP) is a serious health problem that affects millions of people around the world. Additionally, the consequences of CIP include body discomfort, muscle pain, sleep disorders, fatigue, weight gain/loss, digestive system issues and mood disorders. It further influences the people in different ways such as work-productivity loss, job loss, personal relationships, drug-, and alcohol-misuse. According to CDC report, the survey that assessed 20.9% of U.S. adults (51.6 million persons) experienced chronic pain, and 6.9% (17.1 million persons) of experienced high-impact chronic pain during the year 2021.<span style="font-size:10.8333px"> </span>Alternative therapeutic targets are needed for the treatment of these painful conditions.

Nuclear receptors (NRs) are transcription factors activated by ligands and regulate various physiological processes such as metabolism, inflammation, reproduction, and development. NRs constitute significant targets for drug discovery (second only to GPCRs). Among these receptors, REV-ERB is a transcriptional repressor and direct regulator of NLRP3 inflammasome components and proinflammatory cytokines (IL-1β, IL-18), and regulate the activity of macrophages at sites of cellular damage. Up to this point, the precise role of REV-ERB concerning the development of chronic pain symptoms remains unclear. Our interdisciplinary research team is actively working on the development of novel and effective REV-ERB agonists as safe, non-opioid treatments for Chronic Inflammatory Pain (CIP).

In an extension of the recent study, a novel, non-opioid, non-addictive synthetic agonist, STL1267, was developed and evaluated for its efficacy in treating inflammatory pain. The study builds upon existing data, which demonstrates that the activation of the REV-ERB receptor by small molecule ligands (REV-ERB agonists) possesses significant analgesic properties in models of acute inflammatory pain. Recognizing the potent analgesic effects of STL1267, a comprehensive structure-activity relationship (SAR) study was conducted with the aim of discovering novel, potent, and efficacious therapeutics for chronic inflammatory pain. This medicinal chemistry effort is focused on refining STL1267 and exploring its potential as a breakthrough therapeutic target for the long-term management of inflammation-induced pain.

Bahaa Elgendy

Washington University in St Louis

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