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Discovery and first-time disclosure of CVN766, an exquisitely selective orexin 1 receptor antagonist
Angela Glen1, Roland W Bürli2, David Livermore1
1Takeda Cambridge Ltd., 418 Cambridge Science Park, Milton Road, Cambridge CB4 0PZ, UK.
Abstract:
Modulators of orexin receptors are being developed for neurological illnesses such as sleep disorders, addictive behaviours and other psychiatric diseases. We herein describe the discovery of CVN766, a potent orexin 1 receptor antagonist that has greater than 1000-fold selectivity for the orexin 1 receptor over the orexin 2 receptor and demonstrates low off target hits in a diversity screen. In agreement with its in vitro ADME data, CVN766 demonstrated moderate in vivo clearance in rodents and displayed good brain permeability and target occupancy. This drug candidate is currently being investigated in clinical trials for schizophrenia and related psychiatric conditions.
Insights
Researchers discovered CVN766, a selective orexin 1 receptor antagonist, showing promise for neurological disorders. This compound is now in clinical trials for schizophrenia and related psychiatric conditions.
Area of Science:
- Neuroscience
- Pharmacology
- Drug Discovery
Background:
- Orexin receptor modulators are investigated for neurological and psychiatric conditions.
- Existing treatments for sleep disorders, addiction, and psychiatric diseases have limitations.
Purpose of the Study:
- To discover and characterize novel orexin receptor antagonists.
- To identify a drug candidate for treating schizophrenia and related psychiatric disorders.
Main Methods:
- Discovery of CVN766, a selective orexin 1 receptor antagonist.
- In vitro assays for receptor selectivity and off-target screening.
- In vitro ADME studies and in vivo pharmacokinetic/pharmacodynamic evaluation in rodents.
Main Results:
- CVN766 exhibits >1000-fold selectivity for orexin 1 receptor over orexin 2 receptor.
- Low off-target activity observed in diversity screening.
- CVN766 demonstrates moderate clearance, good brain penetration, and target occupancy in vivo.
Conclusions:
- CVN766 is a potent and selective orexin 1 receptor antagonist with favorable drug-like properties.
- CVN766 is a promising clinical candidate for schizophrenia and related psychiatric conditions.
