# Development of Novel Second Generation Anti-inflammatory Substrate-selective p38 MAP Kinase Inhibitors as Therapy for Acute Respiratory Distress Syndrome

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2024 · —

## Abstract

Acute Respiratory Distress Syndrome (ARDS) affects ~190,000 patients and causes ~75,000 deaths per year
in the U.S.A. ARDS has a mortality rate of ~40% and causes significant morbidity in survivors. Respiratory
viruses, including influenza and now Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), are
important causes of ARDS with limited therapeutic options. The VA patient population has many of the risk
factors for having poor outcomes with ARDS, including older age, obesity, hypertension, diabetes, and chronic
lung and heart disease. There are no currently available pharmacologic therapies proven to be effective in
ARDS. To address this need, we developed a novel class of substrate- and function-selective p38 mitogen-
activated protein kinases (MAPK) inhibitors with anti-inflammatory and endothelial-barrier stabilizing activity.
Compared with conventional p38 catalytic inhibitors that block all downstream signaling including anti-
inflammatory pathways, our novel compounds target one of the substrate docking sites and therefore only
block certain p38-dependent processes. Together with my co-investigators, Drs. Shapiro, MacKerell, and
Fletcher, we used computer-aided drug design (CADD) to identify a lead compound, UM101, that binds a
pocket near the ED substrate docking site on p38a and exhibits a unique profile of biological activities. We
developed a second-generation analog, SF7044, with greater solubility and improved endothelial barrier-
stabilizing, anti-inflammatory, and lung-protective activities. We are currently collaborating with Gen1e Life
Sciences, LLC, which licensed the patents for these compounds, completed preclinical testing and began
clinical testing of SF7044. During our current Merit Award, we identified and screened 200 additional
compounds targeted to the same substrate docking site as UM101 using a refined CADD strategy. We
identified four new lead compounds with superior endothelial barrier stabilizing activity and p38a-binding
compared with UM101 and SF7044 and distinct anti-inflammatory effect profiles, but poor solubility. In vivo
testing in a mouse model will require reformulation or chemical modification of these new lead compounds to
improve solubility (like UM101). The overall objective of this renewal is to use the same strategy as used for
development of SF7044 to design, synthesize, and characterize second-generation analogs of the four new
lead compounds with improved activity and drug-like properties. Since the new lead compounds have greater
endothelial-stabilizing activity and p38a-binding than either UM101 or SF7044 we expect to develop second-
generation analogs with substantially improved lung-protective activity. We will utilize CADD and medicinal
chemistry principles, protein binding assays and human cell and mouse models of ALI:
1. Design and synthesize at least 20 analogs of each the 4 newly discovered lead compounds to improve
p38a-binding and drug-like properties.
2. Analyze the second-...

## Key facts

- **NIH application ID:** 10768622
- **Project number:** 5I01BX004270-06
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** JEFFREY D HASDAY
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-07-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10768622

## Citation

> US National Institutes of Health, RePORTER application 10768622, Development of Novel Second Generation Anti-inflammatory Substrate-selective p38 MAP Kinase Inhibitors as Therapy for Acute Respiratory Distress Syndrome (5I01BX004270-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10768622. Licensed CC0.

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