ABSTRACT
High throughput screening identified a phenoxyacetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a compound with functional potency for inhibition of human eosinophil shape change and oral bioavailability in the rat.
Subject(s)
Acetates/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemistry , Animals , Biological Availability , Eosinophils/drug effects , Humans , Rats , Structure-Activity RelationshipABSTRACT
Inhibitors of PDE5 are useful therapeutic agents for treatment of erectile dysfunction. A series of novel xanthine derivatives has been identified as potent inhibitors of PDE5, with good levels of selectivity against other PDE isoforms, including PDE6. Studies in the dog indicate excellent oral bioavailability for compound 21.
Subject(s)
3',5'-Cyclic-GMP Phosphodiesterases/antagonists & inhibitors , Xanthines/pharmacology , Animals , Biological Availability , Cattle , Cyclic Nucleotide Phosphodiesterases, Type 5 , Dogs , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Erectile Dysfunction/drug therapy , Humans , Inhibitory Concentration 50 , Male , Pharmacokinetics , Protein Isoforms/drug effects , Structure-Activity Relationship , Xanthines/chemistryABSTRACT
A series of novel corticosteroid derivatives featuring C-17 furoate ester functionality have been synthesised. Profiling in vitro and in vivo has resulted in the identification of a compound with a longer duration of action and a lower oral side effect profile in rodents compared to budesonide.