# Therapeutic Strategy for NASH

> **NIH NIH R41** · ARTIAM BIO INC. · 2021 · $256,475

## Abstract

Abstract: Therapeutic Strategy for NASH
The overall goal of this project is to identify for clinical development a peripherally selective neutral antagonist
of the CB1 receptor for non-alcoholic steatohepatitis (NASH). Non-alcoholic fatty liver disease (NAFLD)
associated with metabolic syndrome (MetS) can progress to NASH, which is a serious disease without an FDA-
approved drug. There is a strong correlation between severity of NAFLD and development of NASH, which
indicate that decreasing fatty liver (steatosis) is a legitimate strategy for NASH. Compounds that antagonize the
CB1 receptor provide many benefits in MetS through both central nervous system (CNS) and peripheral
mechanisms. Importantly, resolution of NAFLD is achievable by targeting hepatic CB1 receptors, thereby
decreasing de novo lipogenesis and increasing fatty acid oxidation. Competitive orthosteric antagonists can be
either inverse agonists that block basal receptor activity or neutral/silent antagonists that are devoid of this
effect. Previous attempts to target CB1 using inverse agonists led to psychiatric adverse effects in some patients
as the CB1 receptor is involved in reward processing within the CNS. Suppression of basal receptor activity
possibly caused exacerbation of dysphoric effects. Presently, efforts are underway to produce CNS-sparing
inverse agonists to target peripheral CB1 receptors. However, a complicating factor with this strategy is that the
blood-brain barrier that protects the brain is not continuous and chronic use of peripheral inverse agonists still
has the possibility of producing adverse effects. Artiam Bio has produced neutral antagonists of the CB1 receptor
with limited brain penetration. These compounds have the dual advantage of reduced brain penetration coupled
with lack of suppressive effects on basal receptor activity. This approach represents a much-improved strategy
for targeting the CB1 receptor for NASH and other important diseases. Three aims are proposed: (1) ADMET
characterization of the ligands, off-target receptor screening and pharmacokinetic profiling. (2) Establish efficacy
by testing Artiam's best compound in a diet-induced model of NASH that is relevant to the human condition. (3)
Behavioral testing of the lead candidate in two different assays using a chronic dosing regimen to establish an
acceptable safety profile compared to a classical inverse agonist of CB1. Successful completion of these studies
will lead to identification of a first in class, behaviorally de-risked, clinical development candidate for NASH
targeting the CB1 receptor.

## Key facts

- **NIH application ID:** 10323904
- **Project number:** 1R41DK130765-01
- **Recipient organization:** ARTIAM BIO INC.
- **Principal Investigator:** HERBERT H SELTZMAN
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $256,475
- **Award type:** 1
- **Project period:** 2021-09-21 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10323904

## Citation

> US National Institutes of Health, RePORTER application 10323904, Therapeutic Strategy for NASH (1R41DK130765-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10323904. Licensed CC0.

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