Synthesis, structure-activity relationships, and pharmacological profile of 9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6, 7,1-hi]indoles: discovery of potent, selective phosphodiesterase type 4 inhibitors

J Med Chem. 2000 Dec 14;43(25):4850-67. doi: 10.1021/jm000315p.

Abstract

The synthesis, structure-activity relationships, and biological properties of a novel series of potent and selective phosphodiesterase type 4 (PDE4) inhibitors are described. These new aminodiazepinoindoles displayed in vitro PDE4 activity with submicromolar IC(50) values and PDE4 selectivity vs PDE1, -3, and -5. Specifically, one compound (CI-1044, 10e) provided efficient in vitro inhibition of TNFalpha release from hPBMC and hWB with IC(50) values of 0.34 and 0.84 microM, respectively. This compound was found to exhibit potent in vivo activity in antigen-induced eosinophil recruitment in Brown-Norway rats (ED(50) = 3.2 mg/kg po) and in production of TNFalpha in Wistar rats (ED(50) = 2.8 mg/kg po). No emetic side effects at therapeutic doses were observed in ferrets.

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Animals
  • Anti-Asthmatic Agents / adverse effects
  • Anti-Asthmatic Agents / chemical synthesis*
  • Anti-Asthmatic Agents / chemistry
  • Anti-Asthmatic Agents / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Aorta / enzymology
  • Azepines / chemical synthesis*
  • Azepines / chemistry
  • Azepines / metabolism
  • Azepines / pharmacology
  • Binding, Competitive
  • Brain / metabolism
  • Bronchoalveolar Lavage
  • Cell Line
  • Cyclic Nucleotide Phosphodiesterases, Type 1
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Dogs
  • Eosinophils / pathology
  • Ferrets
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Indoles / adverse effects
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Isoenzymes / antagonists & inhibitors
  • Male
  • Monocytes / enzymology
  • Niacinamide / analogs & derivatives
  • Niacinamide / chemical synthesis*
  • Niacinamide / chemistry
  • Niacinamide / metabolism
  • Niacinamide / pharmacology
  • Ovalbumin / immunology
  • Phosphodiesterase I
  • Phosphodiesterase Inhibitors / adverse effects
  • Phosphodiesterase Inhibitors / chemical synthesis*
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacology
  • Phosphoric Diester Hydrolases / metabolism
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship
  • Trachea / enzymology
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Vomiting / chemically induced

Substances

  • Anti-Asthmatic Agents
  • Anti-Inflammatory Agents, Non-Steroidal
  • Azepines
  • Indoles
  • Isoenzymes
  • Phosphodiesterase Inhibitors
  • Tumor Necrosis Factor-alpha
  • Niacinamide
  • Ovalbumin
  • Phosphoric Diester Hydrolases
  • Phosphodiesterase I
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 1
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • PDE5A protein, human
  • Pde5a protein, rat
  • CI 1044