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Fragment-Based Discovery of Pyrimido[1,2-b]indazole PDE10A Inhibitors.

Authors
  • Chino, Ayaka1
  • Seo, Ryushi1
  • Amano, Yasushi1
  • Namatame, Ichiji1
  • Hamaguchi, Wataru1
  • Honbou, Kazuya1
  • Mihara, Takuma1
  • Yamazaki, Mayako1
  • Tomishima, Masaki1
  • Masuda, Naoyuki1
  • 1 Drug Discovery Research, Astellas Pharma Inc.
Type
Published Article
Journal
Chemical and Pharmaceutical Bulletin
Publisher
Pharmaceutical Society of Japan
Publication Date
Jan 01, 2018
Volume
66
Issue
3
Pages
286–294
Identifiers
DOI: 10.1248/cpb.c17-00836
PMID: 29491261
Source
Medline
Keywords
License
Unknown

Abstract

In this study, we report the identification of potent pyrimidoindazoles as phosphodiesterase10A (PDE10A) inhibitors by using the method of fragment-based drug discovery (FBDD). The pyrazolopyridine derivative 2 was found to be a fragment hit compound which could occupy a part of the binding site of PDE10A enzyme by using the method of the X-ray co-crystal structure analysis. On the basis of the crystal structure of compound 2 and PDE10A protein, a number of compounds were synthesized and evaluated, by means of structure-activity relationship (SAR) studies, which culminated in the discovery of a novel pyrimidoindazole derivative 13 having good physicochemical properties.

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