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Discovery of ONO-8590580: a novel, potent and selective GABAA α5 negative allosteric modulator for the treatment of cognitive disorders.

Authors
  • Lewis, A1
  • Beresford, A1
  • Chambers, M S1
  • Clark, G1
  • Hartley, D C1
  • Hirst, K L1
  • Higashino, M2
  • Kawahadara, S2
  • Nakanishi, M2
  • Saito, T2
  • Imagawa, A2
  • Habashita, H2
  • Maidment, S1
  • Macleod, A M1
  • Owens, A P1
  • Rae, A3
  • Rouse, C1
  • Wishart, G1
  • 1 Charles River Discovery Research Services, Chesterford Research Park, Little Chesterford, Essex, CB10 1XL.
  • 2 Ono Pharmaceutical Co. Ltd., Minase Research Institute, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan. , (Japan)
  • 3 Charles River Discovery Research Services, Chesterford Research Park, Little Chesterford, Essex, CB10 1XL. Electronic address: [email protected]
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Sep 05, 2020
Pages
127536–127536
Identifiers
DOI: 10.1016/j.bmcl.2020.127536
PMID: 32898695
Source
Medline
Language
English
License
Unknown

Abstract

The identification and SAR development of a series of negative allosteric modulators of the GABAA α5 receptor is described. This novel series of compounds was optimised to provide analogues with high GABAA α5 binding affinity, high α5 negative allosteric modulatory activity, good functional subtype selectivity and low microsomal turnover, culminating in identification of ONO-8590580. Copyright © 2020 Elsevier Ltd. All rights reserved.

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