title: Design, synthesis, and biological evaluation of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent, orally active, brain penetrant inhibitor of phosphodiesterase 5 (PDE5).
abstract: We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound has recently entered clinical trials.
authors.affiliation: Pfizer Global Research and Development, Chesterfield Parkway West, St Louis, Missouri 63017, USA. Robert.O.Hughes@pfizer.com
authors.forename: Robert O
authors.initials: RO
authors.lastname: Hughes
authors.forename: D Joseph
authors.initials: DJ
authors.lastname: Rogier
authors.forename: E Jon
authors.initials: EJ
authors.lastname: Jacobsen
authors.forename: John K
authors.initials: JK
authors.lastname: Walker
authors.forename: Alan
authors.initials: A
authors.lastname: Macinnes
authors.forename: Brian R
authors.initials: BR
authors.lastname: Bond
authors.forename: Lena L
authors.initials: LL
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Rumsey
authors.forename: Jennie L
authors.initials: JL
authors.lastname: Walgren
authors.forename: Sandra W
authors.initials: SW
authors.lastname: Curtiss
authors.forename: Yvette M
authors.initials: YM
authors.lastname: Fobian
authors.forename: Steven E
authors.initials: SE
authors.lastname: Heasley
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Cubbage
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Moon
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: Brent V
authors.initials: BV
authors.lastname: Mischke
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: Alan G
authors.initials: AG
authors.lastname: Benson
authors.forename: Rhadika M
authors.initials: RM
authors.lastname: Blevis-Bal
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008297:Male; D008956:Models, Chemical; D015394:Molecular Structure; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011719:Pyrazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley
chemical_list: C549061:3-(4-(2-hydroxyethyl)piperazin-1-yl)-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido(3,4-b)pyrazin-2(1H)-one; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011719:Pyrazines; D011725:Pyridines; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5