Novel Treatment of Irritable Bowel Syndrome (IBS) and Other Disorders of the Peripheral Nervous System Using Peripherally Restricted Positive Allosteric Modulators of GABA‑A Receptor

Abstract

The invention in this patent application relates to 6,9-dihydro-5H-imidazo­[1,2-a]­[1,4]­diazepine derivatives (or their N-oxides) represented herein by formula 1. These compounds are peripherally restricted, positive allosteric modulators of one or more GABA-A receptors. They selectively target the peripheral nervous system and body organs and do not substantially penetrate the blood–brain barrier. Thus, they may provide useful treatment for irritable bowel syndrome and other related peripheral disorders, including, but not limited to, functional abdominal pain, chronic idiopathic diarrhea, visceral pain syndromes, inflammatory bowel diseases, bile acid malabsorption, and drug-induced gastrointestinal dysmotility.

Important Compound Classes

Title

Peripherally Restricted GABA Positive Allosteric Modulators for the Treatment of Irritable Bowel Syndrome and Other Ailments of the Peripheral Nervous System. https://patents.google.com/patent/US20260042763A1/en?oq=US+2026%2f0042763+Al

Patent Publication Number

US 2026/0042763 Al

Publication Date

February 12, 2026

Priority Application

US 63/370,325

Priority Date

August 3, 2022

Inventors

Barrow, J. C.; Buchler, I.; Huang, Y.; Poslusney, M.; Pasricha, P. J.

Assignee Company

The Johns Hopkins University, Baltimore, MD (US); Lieber Institute, Inc., Baltimore, MD (US)

Disease Area

Irritable Bowel Syndrome and other systemic diseases in which modulation of one or more peripherally restricted GABA-A receptors is beneficial.

Biological Target

Peripherally restricted positive allosteric modulation of GABA-A receptors

Summary

Irritable bowel syndrome (IBS) is a functional disorder that is characterized by intermittent debilitating abdominal pain associated with altered bowel movements in the absence of a known structural or inflammatory cause. It is a highly prevalent medical disorder that affects an estimated 6–20% of the population in most developed countries. Patients with IBS suffer from significantly diminished quality of life, and IBS causes socioeconomic costs estimated in the billions of dollars annually. IBS patients are clinically classified, based on the dominant bowel pattern (diarrhea or constipation), into three categories: diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), and mixed diarrhea and constipation (IBS-M). Currently, there are only two approved drugs (lubiprostone and linaclotide) that may be prescribed for relieving the symptoms of IBS-C; however, both drugs are secretagogues, meaning they are secretion inducer that act essentially as local laxatives and relief constipation by an aggressive physical influx of water and salt into the gut. Lubiprostone may frequently cause nausea and transient dyspnea. Similarly, the approved prescription drug, linaclotide for the treatment of IBS-D causes frequent abdominal pain, gas, and bloating. Approved prescription drugs for treatment of IBS-D such as eluxadoline only provide symptomatic relief with no demonstrated effects on abdominal pain and also runs the risk of severe pancreatitis.

While the pathogenesis of different forms of irritable bowel syndrome remains incompletely understood, hyperexcitability of both extrinsic (spinal) and intrinsic (enteric) neurons is widely recognized as a primary driver of chronic visceral hypersensitivity and altered gastrointestinal motility. Clinically, IBS patients exhibit heightened colonic myoelectrical activity relative to healthy controls, both at baseline and after a meal. Consequently, suppressing this peripheral neuronal excitability represents a rational therapeutic target for the treatment of IBS.

Historically, most pharmacological approaches for the treatment of IBS have centered on mucosal serotonin [5-hydroxytryptamine (5-HT)] signaling. Specialized mucosal enterochromaffin cells release 5-HT in response to chemical and mechanical stimuli. This, in turn, activates intrinsic primary afferent neurons (IPANs) and nociceptive fibers within the enteric nervous system (ENS) to initiate secretory and motility reflexes. Unfortunately, approved 5-HT receptor modulators have demonstrated only modest efficacy coupled with severe systemic adverse effects. For example, alosetron (a 5-HT₃ receptor antagonist for IBS-D) was restricted due to life-threatening ischemic colitis (fatal lack of blood flow to the colon) and severe constipation, whereas tegaserod (a 5-HT₄ receptor agonist for IBS-C) was withdrawn from the general market following occurrences of cardiovascular ischemic events, including myocardial infarction and stroke.

As an alternative to serotonergic pathways, the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) has drawn significant interest. Activation of neuronal GABA receptors induces cellular hyperpolarization and stabilization of neuronal excitability. GABAergic neurons and both ionotropic (GABA-A) and metabotropic (GABA-B) receptors are abundant throughout the enteric nervous system (ENS) [frequently referred to as the body’s “second brain”] where they mediate distinct functional effects. While preclinical models demonstrated that GABA-B receptor agonists could reduce visceral pain and relax enteric smooth muscle, their clinical development was halted because they readily cross the blood–brain barrier (BBB), promoting severe central nervous system (CNS) adverse effects, including profound sedation, dizziness, and paradoxical gastrointestinal stagnation. Traditional brain-penetrant GABA-A modulators (e.g., classical benzodiazepines like diazepam) were similarly clinically limited by sedation, cognitive impairment, and physical dependence risks.

These cumulative clinical setbacks of serotonin modulators, systemic GABA-B agonists, and other brain-penetrating compounds, such as diazepam, underscore a critical unmet need for safer, non-sedating, and peripherally targeted therapies. The therapeutic application of classical GABA-A receptor positive allosteric modulators (PAMs) has historically been confined to treating CNS conditions such as anxiety, insomnia, and epilepsy, and they have not been applied to IBS treatment. The invention described in this patent application addresses this unmet need by introducing the novel compounds of Formula 1, which function as peripherally restricted positive allosteric modulators of the GABA-A receptor. Unlike direct agonists or central modulators, these positive allosteric modulators enhance natural GABA activity exclusively outside the CNS, as they do not substantially cross the blood–brain barrier. By confining their activity to peripheral organs and the ENS, they provide localized suppression of neuronal hyperactivation, offering a potentially highly effective and targeted treatment for IBS while avoiding the CNS-mediated adverse effects. In addition, the inventors noted that these compounds may possess broader therapeutic utility for treating other related peripheral disorders, including, but not limited to, functional abdominal pain, chronic idiopathic diarrhea, visceral pain syndromes, inflammatory bowel diseases, bile acid malabsorption, and drug-induced gastrointestinal dysmotility.

Key Structures

The inventors described structures and methods of synthesis of 56 examples of formula 1. The following compounds are selected representative examples of formula 1 compounds:

Biological Assay

Investigation of the modulatory effects of the compounds of formula 1 using cells stably transfected with GABA-activated channels of the GABA _A (α₃β₂γ₂) subtype together with submaximal GABA concentrations. Data from this assay are shown below.

In addition, the following assays were only described generally without compounds-specific data:

• Effects of the Compounds and Methods of this Disclosure on Whole Gut Transit Time

• Effects on Distal Colon Transit Time

• Effects on Stool Composition

• Pain Sensitivity in IBS Mouse Model

• Measurement of Brain and Plasma Levels

• Measurement of GABA-A Binding

Biological Data

The biological data obtained from testing the above representative examples of formula 1 are listed in the following table as the concentration of compounds at half maximal effect (EC ₅₀ ) in nM, and the maximum efficacy (E _max or the upper asymptote) as a percentage (%) relative to a specific control baseline. The following key applies to the presented data in the table:

EC ₅₀ : + = >100 nM; ++ = 50–100 nM; +++ = <50 nM

E _max : + = <50%; ++ = 50–100%; +++ = >100%.

Claims

claims 1–66 are general composition of matter claims; claim 67–68 claiming specific examples of formula 1 compounds; claims 69–73 methods of positively modulating GABA-A receptors and treating diseases related to these receptors.

Recent Review Articles

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The author declares no competing financial interest.

Published as part of ACS Medicinal Chemistry Letters special issue “Allosteric Modulators in Drug Discovery”.