Design, synthesis, and biological activities of new thieno[3,2-d] pyrimidines as selective type 4 phosphodiesterase inhibitors

J Med Chem. 1998 Oct 8;41(21):4021-35. doi: 10.1021/jm981012m.

Abstract

A common pharmacophore for compounds structurally related to nitraquazone has been derived. Using this pharmacophore, new structures have been designed, synthesized, and evaluated for their inhibitory potencies against cyclic adenosine 5'-monophosphate (cAMP) specific phosphodiesterase (PDE 4). From these compounds, 4-benzylamino-2-butylthieno[3,2-d]pyrimidine (4) was selected for optimization. The effects of changes to the lipophilic groups and the amino linkage on the PDE 4 activity have been investigated. As a result, some potent PDE 4 inhibitors, selective with respect to PDE 3, have been identified. A selected group of compounds have been further evaluated for their ability to displace [3H]rolipram from its binding site and also to potentiate isoprenaline-induced cAMP accumulation in isolated guinea pig eosinophils. Of these, 2-butyl-4-cyclohexylaminothieno[3,2-d]pyrimidine (33) has an interesting profile, with an important improvement in PDE 4/[3H]rolipram ratio with respect to reference drugs, and good activity in cAMP potentiation, consistent with efficient cell penetration.

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / metabolism*
  • Animals
  • Anti-Asthmatic Agents / chemical synthesis*
  • Anti-Asthmatic Agents / chemistry
  • Anti-Asthmatic Agents / metabolism
  • Anti-Asthmatic Agents / pharmacology
  • Binding, Competitive
  • Cyclic AMP / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Eosinophils / drug effects
  • Eosinophils / metabolism
  • Guinea Pigs
  • In Vitro Techniques
  • Male
  • Models, Molecular
  • Myocardium / enzymology
  • Phosphodiesterase Inhibitors / chemical synthesis*
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / metabolism
  • Phosphodiesterase Inhibitors / pharmacology
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology
  • Pyrrolidinones / metabolism
  • Rolipram
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis*
  • Thiophenes / chemistry
  • Thiophenes / metabolism
  • Thiophenes / pharmacology

Substances

  • 2-butyl-4-cyclohexylaminothieno(3,2-d)pyrimidine
  • Anti-Asthmatic Agents
  • Phosphodiesterase Inhibitors
  • Pyrimidines
  • Pyrrolidinones
  • Thiophenes
  • Cyclic AMP
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Rolipram