# PTPRD phosphatase inhibitors for stimulant use disorders

> **NIH NIH UG3** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $155,345

## Abstract

Summary/abstract: Stimulants provide major challenges in the US. In a recent year, almost 7.5 million
Americans reported cocaine or methamphetamine use. More than 32 million amphetamine prescriptions were
written for conditions including attention deficit hyperactivity disorder and narcolepsy. 1.75 million Americans
reported amphetamine or cocaine use disorders. There were > 212,000 admissions to stimulant use disorder
treatment programs. However, there is no FDA-approved stimulant use disorder pharmacotherapeutic.
The receptor type protein tyrosine phosphatase D (PTPRD) is a novel target for new drugs that reduce reward
from stimulants, thus aiding treatment of stimulant use disorders. We have developed pentilludin (NHB1109), a
novel PTPRD phosphatase inhibitor, to advance to clinical use based on work with > 70 novel analogs.
Pentilludin inhibits PTPRD phosphatase with Ki 700 nM potency. It is covered by a nonprovisional patent
application filed with USPO. Pretreatments with 20 mg/kg pentilludin reduce rat amphetamine self
administration and reduce mouse cocaine-conditioned place preferenc. Pentilludin displays good selectivity vs
sites of EUROFINS screens and phosphatases that include PTP1B. It provides good results in studies of its
carcinogenicity, hERG channel effects, CYP activities and CYP induction. It is metabolized in plasma >>
hepatic microsomes and competes for activity of recombinant paraoxonases, supporting its role as a substrate
for these plasma enzymes. Repeated administration of doses > 150 mg/kg po to mice reduce oral intake and
provide weight loss. There is no toxicity noted in dogs, rats or mice repeatedly dosed with 15, 75 and 100
mg/kg/d, respectively (chemistry, hematology or histopathology except idiosyncratic rodent renal tubular
basophilic lesions not seen in dogs, a pattern found with many drugs that provide no human toxicity).
This supplement to UG3 support will move pentilludin closer to the threshold of first use in humans. It will
allow us to add additional doses to our GLP studies in dogs and rats, heeding the advice of consultants that
FDA will wish to see toxicities (reduced oral intake) in GLP as well as non GLP studies. We will continue to
work with NIDA staff, experienced consultants and preIND meetings with FDA officials to complete an efficient
series of IND-enabling research laboratory and GLP studies. Our GLP studies that will confirm nonGLP results
re pentilludin biodistribution, pharmacodynamics and half-life/metabolism at NOAEL and toxic dose levels in
rats and dogs in GLP studies. These data, as well as validation of final step GMP pentilludin syntheses that
optimize purity and yield (with FDA approval) will provide a strong basis for an IND for pentilludin use in human
phase I studies. These supplemental funds will thus aid our ability to reach milestones for the end of the UG3
support period: holding a preIND meeting with FDA staff and addressing each of the FDA concerns that result
from this meeti...

## Key facts

- **NIH application ID:** 10915221
- **Project number:** 3UG3DA056039-02S2
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** George Richard Uhl
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $155,345
- **Award type:** 3
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10915221

## Citation

> US National Institutes of Health, RePORTER application 10915221, PTPRD phosphatase inhibitors for stimulant use disorders (3UG3DA056039-02S2). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10915221. Licensed CC0.

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