title: Optimization of the aminopyridopyrazinones class of PDE5 inhibitors: discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one.
abstract: We describe efforts to improve the pharmacokinetic profile of the aminopyridopyrazinone class of PDE5 inhibitors. These efforts led to the discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent and selective inhibitor of PDE5 with an excellent PK profile.
authors.affiliation: Pfizer Global Research and Development, Chesterfield Parkway West, St. Louis, MO 63017, USA. robert.o.hughes@pfizer.com
authors.forename: Robert O
authors.initials: RO
authors.lastname: Hughes
authors.forename: John K
authors.initials: JK
authors.lastname: Walker
authors.forename: D Joseph
authors.initials: DJ
authors.lastname: Rogier
authors.forename: Steve E
authors.initials: SE
authors.lastname: Heasley
authors.forename: Rhadika M
authors.initials: RM
authors.lastname: Blevis-Bal
authors.forename: Alan G
authors.initials: AG
authors.lastname: Benson
authors.forename: E Jon
authors.initials: EJ
authors.lastname: Jacobsen
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Cubbage
authors.forename: Yvette M
authors.initials: YM
authors.lastname: Fobian
authors.forename: Dafydd R
authors.initials: DR
authors.lastname: Owen
authors.forename: John N
authors.initials: JN
authors.lastname: Freskos
authors.forename: John M
authors.initials: JM
authors.lastname: Molyneaux
authors.forename: David L
authors.initials: DL
authors.lastname: Brown
authors.forename: Brad A
authors.initials: BA
authors.lastname: Acker
authors.forename: Todd M
authors.initials: TM
authors.lastname: Maddux
authors.forename: Mike B
authors.initials: MB
authors.lastname: Tollefson
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Moon
authors.forename: Brent V
authors.initials: BV
authors.lastname: Mischke
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Rumsey
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: Alan
authors.initials: A
authors.lastname: MacInnes
authors.forename: Brian R
authors.initials: BR
authors.lastname: Bond
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
mesh_terms: D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D020033:Protein Isoforms; D011719:Pyrazines; D011725:Pyridines; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6