7-Oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridines as novel inhibitors of human eosinophil phosphodiesterase

J Med Chem. 1998 Jun 18;41(13):2268-77. doi: 10.1021/jm9800090.

Abstract

High-throughput file screening against inhibition of human lung PDE4 led to the discovery of 3-ethyl-1-(4-fluorophenyl)-6-phenyl-7-oxo-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (11) as a novel PDE4 inhibitor. Subsequent SAR development, using an eosinophil PDE assay, led to analogues up to 50-fold more potent than 11 with IC50 values of 0.03-1.6 microM. One such compound, CP-220,629 (22) (IC50 = 0.44 microM), was efficacious in the guinea pig aerosolized antigen induced airway obstruction assay (ED50 2.0 mg/kg, po) and demonstrated a significant reduction in eosinophil (55%), neutrophil (65%), and IL-1beta (82%) responses to antigen challenge in atopic monkeys (10 mg/kg, po).

Publication types

  • Comparative Study

MeSH terms

  • Airway Obstruction / immunology
  • Airway Obstruction / metabolism
  • Airway Obstruction / pathology
  • Airway Obstruction / prevention & control
  • Animals
  • Anti-Asthmatic Agents* / chemical synthesis
  • Anti-Asthmatic Agents* / chemistry
  • Anti-Asthmatic Agents* / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal* / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal* / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal* / pharmacology
  • Bronchoalveolar Lavage Fluid / cytology
  • Bronchoalveolar Lavage Fluid / immunology
  • Cell Count / drug effects
  • Cell Line
  • Cyclic AMP / metabolism
  • Cytokines / metabolism
  • Dihydropyridines* / chemical synthesis
  • Dihydropyridines* / chemistry
  • Dihydropyridines* / pharmacology
  • Drug Evaluation, Preclinical
  • Eosinophils / drug effects
  • Eosinophils / enzymology*
  • Eosinophils / immunology
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Isoenzymes / antagonists & inhibitors*
  • Macaca fascicularis
  • Molecular Conformation
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Ovalbumin / immunology
  • Phosphodiesterase Inhibitors* / chemical synthesis
  • Phosphodiesterase Inhibitors* / chemistry
  • Phosphodiesterase Inhibitors* / pharmacology
  • Phosphoric Diester Hydrolases / metabolism*
  • Pyrazoles* / chemical synthesis
  • Pyrazoles* / chemistry
  • Pyrazoles* / pharmacology
  • Pyrrolidinones / pharmacology
  • Rolipram
  • Structure-Activity Relationship

Substances

  • Anti-Asthmatic Agents
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cytokines
  • Dihydropyridines
  • Isoenzymes
  • Phosphodiesterase Inhibitors
  • Pyrazoles
  • Pyrrolidinones
  • Ovalbumin
  • CP 220629
  • Cyclic AMP
  • Phosphoric Diester Hydrolases
  • Rolipram