title: Synthesis and biological activity of pyrido[3',2':4,5]furo[3,2-d]pyrimidine derivatives as novel and potent phosphodiesterase type 4 inhibitors.
abstract: A series of pyrido[3',2':4,5]furo[3,2-d]pyrimidines (PFP) were synthesized and tested for phosphodiesterase type 4 (PDE4) inhibitory activity, with the potential to treat asthma and chronic obstructive pulmonary disease (COPD). Structure-activity relationships within this series, leading to an increase of potency on the enzyme, is presented. Both gem-dimethylcyclohexyl moieties fused to the pyridine ring and the substitution at the 5 position of the PFP scaffold, proved to be key elements in order to get a high affinity in the enzyme.
authors.affiliation: Department of Medicinal Chemistry, Almirall S.A., R&D Centre, Laureà Miró 408-410, 08980 Sant Feliu de Llobregat, Catalonia, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Taltavull
authors.forename: Jordi
authors.initials: J
authors.lastname: Serrat
authors.forename: Jordi
authors.initials: J
authors.lastname: Gràcia
authors.forename: Amadeu
authors.initials: A
authors.lastname: Gavaldà
authors.forename: Mònica
authors.initials: M
authors.lastname: Córdoba
authors.forename: Elena
authors.initials: E
authors.lastname: Calama
authors.forename: José Luis
authors.initials: JL
authors.lastname: Montero
authors.forename: Míriam
authors.initials: M
authors.lastname: Andrés
authors.forename: Montserrat
authors.initials: M
authors.lastname: Miralpeix
authors.forename: Dolors
authors.initials: D
authors.lastname: Vilella
authors.forename: Begoña
authors.initials: B
authors.lastname: Hernández
authors.forename: Jorge
authors.initials: J
authors.lastname: Beleta
authors.forename: Hamish
authors.initials: H
authors.lastname: Ryder
authors.forename: Lluís
authors.initials: L
authors.lastname: Pagès
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D005289:Ferrets; D006801:Humans; D008958:Models, Molecular; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000201:enzymology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D011743:Pyrimidines; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4