# Preclinical assessment of a novel systemic drug candidate for osteoarthritic pain

> **NIH NIH R61** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2023 · $1,348,453

## Abstract

ABSTRACT
Osteoarthritis (OA), also known as degenerative joint disease, is a progressive disease that eventually leads to
a functional disability making it the 11th most debilitating ailment worldwide and one of the greatest pressing
current issues in public health. The most notable clinical symptom of OA is chronic joint pain that is gradual in
onset and that worsens over time. The pain-related functional impairment is characterized by interference with
many aspects of daily activity significantly decreasing quality of life. Despite reserved controversial
recommendations by current guidelines due to dependency, abuse, tolerability and toxicity concerns, opioids are
frequently prescribed for pain control when other pain management options have failed. The negative
consequences of opioids evince a necessity for alternative route options for OA pain management. OA is a
multifactorial disorder, which involves low-grade, chronic inflammation that is mediated, in part, by interleukin-
6/glycoprotein 130 (IL-6/gp130) cascade leading to gradual matrix degradation and irreversible destruction of
articular cartilage. Recent studies have reported that IL-6/gp130 signaling is implicated in the development of
inflammatory, pathological pain. Previously, we have demonstrated that manipulation of intracellular residues
within gp130 receptor and its context specific downstream signaling can be deconstructed to selectively bypass
the pro-inflammatory consequences of this axis while promoting beneficial outcomes. Our group has identified a
signaling residue (Y814) within gp130 that represents an initiating factor responsible for the activation of a highly
detrimental arm of gp130 and constitutive ablation of Y814 in mice inhibits development of injury-induced OA.
To manipulate the destructive outputs downstream of gp130, including those regulated by Y814, we have
synthesized a new class of small molecule compounds capable of selective inactivation of gp130 signaling and
consequently protect articular cartilage in the knee from matrix degradation and reduce pain in rat and canine
models of post-traumatic OA. Through multiple rounds of optimization, an analog that we termed R159 has
shown the most potent and selective inhibition of gp130Y814 as well as an excellent absorption, distribution,
metabolism, and excretion (ADME) profile. Current grant application is designed to systematically investigate
the significance of gp130Y814 in the pathogenesis of OA and interrogate whether pharmacologically targeting this
residue will attenuate OA-associated chronic pain. For this, we will first define the systemic pharmacokinetic
parameters for R159 after oral and intraperitoneal administration to rats. Subsequently, we will determine the
efficacy of systemically administered R159 in mitigating pain and functional and affective behaviors in a pre-
clinical CFA-induced ankle OA rat and generalized OA guinea pig models. No conducted clinical trials till date
have provided adequa...

## Key facts

- **NIH application ID:** 10642544
- **Project number:** 1R61NS131307-01
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** DENIS EVSEENKO
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,348,453
- **Award type:** 1
- **Project period:** 2023-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10642544

## Citation

> US National Institutes of Health, RePORTER application 10642544, Preclinical assessment of a novel systemic drug candidate for osteoarthritic pain (1R61NS131307-01). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10642544. Licensed CC0.

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