# PTPRD phosphatase inhibitors for stimulant use disorders

> **NIH NIH UG3** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $1,453,896

## Abstract

Specific Aims: Illicit and prescribed 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 disorders including attention deficit hyperactivity disorder and narcolepsy. 1.75
million Americans reported cocaine or amphetamine or use disorders. There were more than 212,000
admissions to stimulant use disorder treatment programs. A “fourth wave” of US drug overdose deaths
includes many individuals who use stimulants. However, individuals who seek to quit stimulant use have no
pharmacological treatment approved by FDA. Medication development portfolios aimed at treating stimulant
use disorders should include new drugs acting at novel targets that are as well-supported as possible, a priori,
by human and other data.
Robust human, mouse model and pharmacologic data now support PTPRD (receptor type protein tyrosine
phosphatase D) as a novel target for treatment of stimulant use disorders and, perhaps, their prevention.
Human PTPRD genomic variants are associated with: a) vulnerability to develop a stimulant use disorder, b)
the extent of reward from stimulant administration and c) levels of brain PTPRD expression. Mice that express
less PTPRD display less reward from stimulants. We have characterized an initial PTPRD phosphatase
inhibitor, 7-BIA, and a more potent/selective congener, NHB1109.
NHB1109 features support its development as a medication. We can now synthesize NHB1109 readily from
commercially-available precursors. NHB1109 is selective. It displays greater potency at PTPRD than at most
other tyrosine phosphatases. It has no significant activity in EUROFINS screens of targets of current drugs.
NHB1109 is bioavailable in rats after oral dosing. It is relatively stable. It has intellectual property protection. It
substantially reduces cocaine conditioned place preference in wildtype mice, but not in PTPRD knockouts.
Acute or repeated NHB1109 doses up to 300 mg/kg provide no toxicity. Mice survive 2,000 mg/kg gavage
doses, but develop a dose-limiting toxicity, ileus.
This exciting identification of NHB1109 as a novel, potent, selective small molecule PTPRD phosphatase
inhibitor with proof of in vivo pharmacological activity in reducing stimulant reward and a reasonable
therapeutic index leads us to seek Avant Garde support. We will move NHB1109 forward through IND-enabling
work, initial use in humans and completion of phase I human studies. We will continue studies of backup
compounds should NHB 1109 display unanticipated limitations. We will complete antecedents to FDA IND
approval including metabolic, two-species toxicity and carcinogenicity screens. We will receive IND approval
and complete first in human, ascending dose and repeated dose research volunteer studies, including those
with amphetamine challenge doses. We will advance development of NHB1109 to address unmet needs in
treating devastating st...

## Key facts

- **NIH application ID:** 10457132
- **Project number:** 1UG3DA056039-01
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** George Richard Uhl
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,453,896
- **Award type:** 1
- **Project period:** 2022-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457132

## Citation

> US National Institutes of Health, RePORTER application 10457132, PTPRD phosphatase inhibitors for stimulant use disorders (1UG3DA056039-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10457132. Licensed CC0.

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