ABSTRACT
A new series of thienopyrimidinones is synthesized and evaluated as selective phosphodiesterase 7 (PDE7) inhibitors for the treatment of inflammatory diseases. The modification of the substituents on thienopyrimidinone revealed that an isopropylamino group at the 2-position was favorable for aqueous solubility. The introduction of 3-pyrrolidines at the 7-position resulted in good solubility, highly potent activity, and good PDE7 selectivity. Among the synthesized compounds, compound 46 exhibited the greatest inhibition of ear edema in a phorbol ester-induced mouse model.
Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 7/antagonists & inhibitors , Edema/drug therapy , Pyrimidinones/pharmacology , Animals , Cyclic Nucleotide Phosphodiesterases, Type 7/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Edema/chemically induced , Male , Mice , Mice, Inbred ICR , Models, Molecular , Molecular Structure , Phorbol Esters , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Solubility , Structure-Activity Relationship , Substrate SpecificityABSTRACT
The discovery and SAR study of a new series of soluble and highly potent phosphodiesterase (PDE) 7 inhibitors are described herein. We explored a new lead compound with improved solubility, which led to the discovery of a 2-(4-pyridylamino)thieno[3,2-d]pyrimidin-4(3H)-one series. The introduction of 3-piperidines at the 7-position resulted in the significant enhancement of PDE7 activity. In particular, compound 32 also showed strong PDE7 inhibitory activity; good selectivity against PDE3, 4, and 5; and good aqueous solubility.
