ABSTRACT
The anti-inflammatory effects of CI-1044 and of the other selective PDE4 inhibitors rolipram and cilomilast were investigated in Brown-Norway (BN) rats, against lipopolysaccharide-induced tumor necrosis factor alpha (TNFalpha) production in whole blood and antigen-induced lung eosinophilia. In vitro, CI-1044 inhibited TNFalpha production with an IC(50) of 0.31 microm being equipotent to Cilomilast (IC(50) = 0.26 microm) and rolipram (IC(50) = 0.11 microm). Given orally, CI-1044 inhibited ex vivo TNFalpha production with an ED(50) value of 0.4 mg/kg after single administration, whereas rolipram (ED(50) = 1.4 mg/kg) and cilomilast (ED(50) = 1.6 mg/kg) were less potent. In the same ex vivo setting, but given repeatedly, CI-1044 led to an ED(50) of 0.5 mg/kg corresponding to a plasma concentration of 82.6 ng/mL (0.22 microm). In vivo, CI-1044 prevented TNFalpha release with an ED(50) of 1 mg/kg p.o. and inhibited ovalbumin-induced lung eosinophilia following single or repeated oral administration with an ED(50) of 3.25 and 4.8 mg/kg p.o., respectively, suggesting the absence of pharmacological tolerance. CI-1044 in this model was equipotent to rolipram (81% inhibition at 10 mg/kg) but better than cilomilast (25% inhibition at 10 mg/kg). Finally, CI-1044 (10 mg/kg) inhibited inflammatory cell recruitment with a long duration of action (up to 8 h) and was still active when given post-challenge. Our data show that CI-1044 is an orally active PDE4 inhibitor that may be used as an anti-inflammatory therapy in lung inflammatory diseases.
Subject(s)
Azepines/pharmacology , Inflammation/drug therapy , Niacinamide/analogs & derivatives , Phosphodiesterase 4 Inhibitors , Phosphodiesterase Inhibitors/pharmacology , Administration, Oral , Animals , Azepines/administration & dosage , Carboxylic Acids/administration & dosage , Carboxylic Acids/pharmacology , Cyclohexanecarboxylic Acids , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Schedule , Inflammation/physiopathology , Inhibitory Concentration 50 , Lipopolysaccharides , Male , Niacinamide/administration & dosage , Niacinamide/pharmacology , Nitriles/administration & dosage , Nitriles/pharmacology , Phosphodiesterase Inhibitors/administration & dosage , Pulmonary Eosinophilia/drug therapy , Pulmonary Eosinophilia/physiopathology , Rats , Rats, Inbred BN , Rolipram/administration & dosage , Rolipram/pharmacology , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/metabolismABSTRACT
The synthesis and SAR studies of a series of structurally novel small molecule inhibitors of PDE7 are discussed. The best compounds from the series displayed low nanomolar inhibitory activity and are selective versus PDE4.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Isoenzymes/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Thiadiazoles/chemical synthesis , Thiadiazoles/pharmacology , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Cell Line , Cyclic Nucleotide Phosphodiesterases, Type 4 , Cyclic Nucleotide Phosphodiesterases, Type 7 , Humans , Isoenzymes/metabolism , Phosphodiesterase Inhibitors/chemistry , Structure-Activity Relationship , Thiadiazoles/chemistryABSTRACT
The synthesis and SAR studies of spiroquinazolinones as novel PDE7 inhibitors are discussed. The best compounds from the series displayed nanomolar inhibitory affinity and were selective versus other PDE isoenzymes.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Isoenzymes/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemical synthesis , Quinazolines/chemical synthesis , Spiro Compounds/chemical synthesis , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Cell Line , Cyclic Nucleotide Phosphodiesterases, Type 7 , Drug Evaluation, Preclinical , Humans , Isoenzymes/metabolism , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Solubility , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
The optimization of 5,8-disubstituted spirocyclohexane-quinazolinones into potent, selective, soluble PDE7 inhibitors with acceptable in vivo pharmacokinetic parameters is presented.
