Abstract
Provided herein are novel tetrahydropyridinyl-6,6-bicyclic compounds as 5-HT2A receptor agonists, pharmaceutical compositions, use of such compounds in treating depression, anxiety, substance abuse and headaches, and processes for preparing such compounds.
Important Compound Classes
Title
Tetrahydropyridinyl-6,6-Bicyclic 5-HT2AR Agonists and Uses Thereof
Patent Publication Number
WO 2026/074320 A1
Publication Date
April 9, 2026
Priority Application
US 63/703,388; US 63/749,996; US 63/758,426; and US 63/879,174
Priority Date
October 4, 2024; January 27, 2025; February 14, 2025; and September 10, 2025
Inventors
Glossop, P.; Montana, J.; Heal, J.; Cridland, A.; Clayton, R.; Fox, D.
Assignee Company
Brandaris Therapeutics B.V., Netherlands
Disease Area
Depression, anxiety, substance abuse and headaches
Biological Target
5-HT2A
Summary
Agonists of 5-HT2AR may have potential as pharmaceuticals for a variety of neurological diseases including depression, anxiety, substance abuse, migraine headaches and/or cluster headaches. Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. After the discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD) and the identification of serotonin in the brain, early research focused intensively on LSD. Today, there is consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A (5-HT2A) receptors. Psychedelics have both rapid onset and persisting effects, which includes changes in mood and brain function. The classical psychotic agents include LSD, psilocybin or mescaline.
The 5-HT2A receptor plays an important role in emotional responses and is an important target to be considered in the action of 5-HT2A agonist psychedelics. In fact, a majority of known 5-HT2A agonists produce hallucinogenic effects in humans. Psilocybin activates 5HT1A receptors, which may contribute to antidepressant/antianxiety effects.
Psychosis is often referred to as an abnormal state of mind that is characterized by hallucinatory experiences, delusional thinking and disordered thoughts. Anecdotal evidence suggests that low, nonhallucinogenic doses of psychedelics can reduce symptoms of schizophrenia and psychosis.
The present application describes a series of novel tetrahydropyridinyl-6,6-bicyclic compounds as 5-HT2A receptor agonists for the treatment of depression, anxiety, substance abuse and headaches. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.
Definitions
X1 = N, NR1, CR1, or C = O; X2 = N. NR, or CR2; X3 = N, NR, or CR3; X4 = N, NR, CR4, or C = O; X5 = N or CR5; X6 = N or CR6; X7 = N or CR7; wherein at least one of X1 and X2 is N or NR; and
Key Structures
Biological Assay
The human 5-HT2A receptor calcium assay was performed. The compounds described in this application were tested for their ability to bind on human 5-HT2A. The 5-HT2A pEC50 are shown in the following Table.
Biological Data
The Table below shows representative compounds that were tested for binding properties on human 5-HT2A. The biological data obtained from testing representative examples are listed in the following Table.
For pEC50: A means ≥ 6.
Claims
Total claims: 131
Compound claims: 120
Pharmaceutical composition claims: 1
Method of treatment claims: 4
Method of activating claims: 2
Method of selectively activating claims: 2
Method of increasing activation claims: 2
Recent Review Articles
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The authors declare no competing financial interest.
References
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