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.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Anti-Asthmatic Agents/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Azepines/chemical synthesis , Indoles/chemical synthesis , Niacinamide/chemical synthesis , Phosphodiesterase Inhibitors/chemical synthesis , 3',5'-Cyclic-GMP Phosphodiesterases , Animals , Anti-Asthmatic Agents/adverse effects , Anti-Asthmatic Agents/chemistry , Anti-Asthmatic Agents/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Aorta/enzymology , 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/chemistry , Indoles/pharmacology , Isoenzymes/antagonists & inhibitors , Male , Monocytes/enzymology , Niacinamide/analogs & derivatives , Niacinamide/chemistry , Niacinamide/metabolism , Niacinamide/pharmacology , Ovalbumin/immunology , Phosphodiesterase I , Phosphodiesterase Inhibitors/adverse effects , 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 inducedABSTRACT
A novel series of benzodiazepine derivatives have been discovered as inhibitors of PDE4 enzymes. We have found that our compounds are selective versus other PDE enzymes, and that the activity can be modulated by specific structural modifications. One compound exhibited a strong eosinophilic infiltration inhibiting action on sensitized Brown-Norway rats (compound 9, 5.1 mg/kg p.o.), moreover this compound is not emetic at 3 mg/kg i.v.
