title: Identification, synthesis and SAR of amino substituted pyrido[3,2b]pyrazinones as potent and selective PDE5 inhibitors.
abstract: A new class of potent and selective PDE5 inhibitors is disclosed. Guided by X-ray crystallographic data, optimization of an HTS lead led to the discovery of a series of 2-aryl, (N8)-alkyl substituted-6-aminosubstituted pyrido[3,2b]pyrazinones which show potent inhibition of the PDE5 enzyme. Synthetic details and some structure-activity relationships are also presented.
authors.affiliation: Department of Chemistry, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK.
authors.forename: Dafydd R
authors.initials: DR
authors.lastname: Owen
authors.forename: John K
authors.initials: JK
authors.lastname: Walker
authors.forename: E
authors.initials: E
authors.lastname: Jon Jacobsen
authors.forename: John N
authors.initials: JN
authors.lastname: Freskos
authors.forename: Robert O
authors.initials: RO
authors.lastname: Hughes
authors.forename: David L
authors.initials: DL
authors.lastname: Brown
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Bell
authors.forename: David G
authors.initials: DG
authors.lastname: Brown
authors.forename: Christopher
authors.initials: C
authors.lastname: Phillips
authors.forename: Brent V
authors.initials: BV
authors.lastname: Mischke
authors.forename: John M
authors.initials: JM
authors.lastname: Molyneaux
authors.forename: Yvette M
authors.initials: YM
authors.lastname: Fobian
authors.forename: Steve E
authors.initials: SE
authors.lastname: Heasley
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Moon
authors.forename: William C
authors.initials: WC
authors.lastname: Stallings
authors.forename: D
authors.initials: D
authors.lastname: Joseph Rogier
authors.forename: David N A
authors.initials: DN
authors.lastname: Fox
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Palmer
authors.forename: Tracy
authors.initials: T
authors.lastname: Ringer
authors.forename: Margarita
authors.initials: M
authors.lastname: Rodriquez-Lens
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Cubbage
authors.forename: Radhika M
authors.initials: RM
authors.lastname: Blevis-Bal
authors.forename: Alan G
authors.initials: AG
authors.lastname: Benson
authors.forename: Brad A
authors.initials: BA
authors.lastname: Acker
authors.forename: Todd M
authors.initials: TM
authors.lastname: Maddux
authors.forename: Michael B
authors.initials: MB
authors.lastname: Tollefson
authors.forename: Brian R
authors.initials: BR
authors.lastname: Bond
authors.forename: Alan
authors.initials: A
authors.lastname: Macinnes
authors.forename: Yung
authors.initials: Y
authors.lastname: Yu
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D020134:Catalytic Domain; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000737:chemistry*; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000037:antagonists & inhibitors / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011719:Pyrazines; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C406737:PDE11A protein, human