2. Academic Validation
  3. Discovery and first-time disclosure of CVN766, an exquisitely selective orexin 1 receptor antagonist

Discovery and first-time disclosure of CVN766, an exquisitely selective orexin 1 receptor antagonist

  • Bioorg Med Chem Lett. 2024 Mar 1:100:129629. doi: 10.1016/j.bmcl.2024.129629.
Angela Glen 1,  Roland W Bürli 2,  David Livermore 1,  William Buffham 1,  Stephanie Merison 1,  Anna E Rowland 3,  Robert Newman 3,  Charlotte Fieldhouse 1,  David J Miller 1,  Lee A Dawson 2,  Kim Matthews 2,  Mark B Carlton 3,  Nicola L Brice 4
Affiliations

Affiliations

  • 1 Takeda Cambridge Ltd., 418 Cambridge Science Park, Milton Road, Cambridge CB4 0PZ, UK.
  • 2 Cerevance Ltd, 418 Cambridge Science Park, Milton Road, Cambridge CB4 0PZ, UK.
  • 3 Takeda Cambridge Ltd., 418 Cambridge Science Park, Milton Road, Cambridge CB4 0PZ, UK; Cerevance Ltd, 418 Cambridge Science Park, Milton Road, Cambridge CB4 0PZ, UK.
  • 4 Takeda Cambridge Ltd., 418 Cambridge Science Park, Milton Road, Cambridge CB4 0PZ, UK; Cerevance Ltd, 418 Cambridge Science Park, Milton Road, Cambridge CB4 0PZ, UK. Electronic address: [email protected].
PMID: 38295907 DOI: 10.1016/j.bmcl.2024.129629
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.

Keywords

Antagonist; Hypocretin; Orexin; Ox1R.

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