title: Biphenyl Pyridazinone Derivatives as Inhaled PDE4 Inhibitors: Structural Biology and Structure-Activity Relationships.
abstract: Cyclic nucleotide cAMP is a ubiquitous secondary messenger involved in a plethora of cellular responses to biological agents involving activation of adenylyl cyclase. Its intracellular levels are tightly controlled by a family of cyclic nucleotide degrading enzymes, the PDEs. In recent years, cyclic nucleotide phosphodiesterase type 4 (PDE4) has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases, particularly in the management of asthma and COPD. Here we describe our efforts to discover novel, highly potent inhaled inhibitors of PDE4. Through structure based design, with the inclusion of a variety of functional groups and physicochemical profiles in order to occupy the solvent-filled pocket of the PDE4 enzyme, we modified the structure of our oral PDE4 inhibitors to reach compounds down to picomolar enzymatic potencies while at the same time tackling successfully an uncovered selectivity issue with the adenosine receptors. In vitro potencies were demonstrated in a rat lung neutrophilia model by administration of a suspension with a Penn-Century MicroSprayer Aerosolizer.
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Gràcia
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Maria Antonia
authors.initials: MA
authors.lastname: Buil
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Castro
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Peter
authors.initials: P
authors.lastname: Eichhorn
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Ferrer
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Amadeu
authors.initials: A
authors.lastname: Gavaldà
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Hernández
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Segarra
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Lehner
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Imma
authors.initials: I
authors.lastname: Moreno
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Pagès
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Roberts
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Serrat
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Sevilla
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Taltavull
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Andrés
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: Cabedo
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Vilella
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Calama
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Carla
authors.initials: C
authors.lastname: Carcasona
authors.affiliation: Medicinal Chemistry and Screening, ‡Pharmacokinetics and Metabolism, §Experimental Dermatology, and ∥Licensing and Corporate Development, Centro de Investigación y Desarrollo, Almirall S.A. , Crta. Laureà Miró 408-410, Sant Feliu de Llobregat, 08980 Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Miralpeix
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D001713:Biphenyl Compounds; D058988:Phosphodiesterase 4 Inhibitors; D011724:Pyridazines; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4