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2-(Isopropylamino)thieno[3,2-d]pyrimidin-4(3H)-one derivatives as selective phosphodiesterase 7 inhibitors with potent in vivo efficacy.

Abstract
A new series of thienopyrimidinones is synthesized and evaluated as selective phosphodiesterase 7 (PDE7) inhibitors for the treatment of inflammatory diseases. The modification of the substituents on thienopyrimidinone revealed that an isopropylamino group at the 2-position was favorable for aqueous solubility. The introduction of 3-pyrrolidines at the 7-position resulted in good solubility, highly potent activity, and good PDE7 selectivity. Among the synthesized compounds, compound 46 exhibited the greatest inhibition of ear edema in a phorbol ester-induced mouse model.
AuthorsYusuke Endo, Kentaro Kawai, Takeshi Asano, Seiji Amano, Yoshihito Asanuma, Keisuke Sawada, Yuuta Onodera, Noriko Ueo, Nobuaki Takahashi, Yo Sonoda, Noriyuki Kamei, Tetsumi Irie
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 25 Issue 9 Pg. 1910-4 (May 01 2015) ISSN: 1464-3405 [Electronic] England
PMID25866242 (Publication Type: Journal Article)
CopyrightCopyright © 2015 Elsevier Ltd. All rights reserved.
Chemical References
  • 2-(isopropylamino)thieno(3,2-d)pyrimidin-4(3H)-one
  • Phorbol Esters
  • Pyrimidinones
  • Cyclic Nucleotide Phosphodiesterases, Type 7
  • Pde7a protein, mouse
Topics
  • Animals
  • Cyclic Nucleotide Phosphodiesterases, Type 7 (antagonists & inhibitors, metabolism)
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Edema (chemically induced, drug therapy)
  • Male
  • Mice
  • Mice, Inbred ICR
  • Models, Molecular
  • Molecular Structure
  • Phorbol Esters
  • Pyrimidinones (chemical synthesis, chemistry, pharmacology)
  • Solubility
  • Structure-Activity Relationship
  • Substrate Specificity

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