# Prevention of arthritis-induced bone erosion by inhibiting osteoclast differentiation by the haloanilide N-Methyl Dichloropropionaniline

> **NIH NIH R42** · EXESALIBERO, INC. · 2020 · $108,153

## Abstract

We are working on a new approach to treating acute arthritis based on a common pathway in the cellular
infiltrates that damage bones and joints. Inflammatory arthritis disables thousands of people each year. It occurs
in children and adults, after trauma and infections but most cases are idiopathic. Millions of adults live with
chronic RA, which has similar features. Inflammatory arthritis often requires treatments with serious side effects.
Later in arthritis, bone erosion is a major problem that causes severe pain and debilitation. There is no small
molecule drug available to specifically treat arthritic bone erosion. We show that osteoclast maturation is
suppressed by blocking a calcium-release activated calcium channel, called Orai. A Orai antagonist, N-methyl-
3,4-dichloropropionaniline (N-MeDCPA), suppressed osteoclast maturation and strongly suppressed collagen-
induced arthritis (CIA) in mice, even after symptoms of arthritis were measureable. We propose that
pharmacologically suppressing CRAC channels with N-MeDCPA will prevent bone erosion due to arthritic stimuli
without major adverse effects.
 We hypothesize that Ca2+ signals mediated by Orai channels modulate final differentiation of osteoclasts,
and that related effects on T cells might reinforce bone and joint sparing in acute arthritis. We expect toxicity of
N-MeDCPA to be low when treatment is for several weeks in animals with mature immune systems. We propose
comprehensive pharmacokinetic and toxicokinetic testing in addition to mechanistic experiments with Ca2+
signaling, immunology, and bone biology expertise.
 Phase I - AIM 1: - Drug formulation, route of administration optimization and Orai specificity. N-
MeDCPA is lipid soluble. This aim will define a suitable nanoparticle (NP) or liposome formulation of N-
MeDCPA for parenteral or oral administration. Drug blood levels versus ease/convenience and effectiveness will
be assessed.
 Phase I – AIM 2: - Complete the dose-response studies of N-MeDCPA using the CIA model. Having
demonstrated that N-MeDCPA can prevent bone erosion and arrest inflammation in symptomatic mice, the
emphasis of this aim will be to define its effect against the standard CIA measures, arthritic index, bone erosion,
volume by µCT and inflammation (swelling) using the optimized dosing regimen.
 Phase II - AIM 1: Pharmacology and toxicology assessment of N-MeDCPA under non-GLP and GLP
conditions in vitro and in vivo. An extensive suite of tests will be performed by a contract research organization
(CRO) under contract with ExesaLibero (see letter of support from Covance).
 Phase II - AIM 2: Determine the therapeutic-potential of N-MeDCPA. Critical to demonstrating that N-
MeDCPA will improve the standard of care/quality of life, is confirmation of equal effectiveness in both sexes
using SKG mice, determining its cellular specificity, checking for potential immunotoxicity of N-MeDCPA in tests
not covered by the CRO and exploring possible additive/synergisti...

## Key facts

- **NIH application ID:** 10083507
- **Project number:** 3R42AR074812-01A1S1
- **Recipient organization:** EXESALIBERO, INC.
- **Principal Investigator:** John B Barnett
- **Activity code:** R42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $108,153
- **Award type:** 3
- **Project period:** 2019-09-25 → 2020-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10083507

## Citation

> US National Institutes of Health, RePORTER application 10083507, Prevention of arthritis-induced bone erosion by inhibiting osteoclast differentiation by the haloanilide N-Methyl Dichloropropionaniline (3R42AR074812-01A1S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10083507. Licensed CC0.

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