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).
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.
Hughes
Robert O
RO
Pfizer Global Research and Development, Chesterfield Parkway West, St Louis, Missouri 63017, USA. Robert.O.Hughes@pfizer.com
Rogier
D Joseph
DJ
Jacobsen
E Jon
EJ
Walker
John K
JK
Macinnes
Alan
A
Bond
Brian R
BR
Zhang
Lena L
LL
Yu
Ying
Y
Zheng
Yi
Y
Rumsey
Jeanne M
JM
Walgren
Jennie L
JL
Curtiss
Sandra W
SW
Fobian
Yvette M
YM
Heasley
Steven E
SE
Cubbage
Jerry W
JW
Moon
Joseph B
JB
Brown
David L
DL
Acker
Brad A
BA
Maddux
Todd M
TM
Tollefson
Mike B
MB
Mischke
Brent V
BV
Owen
Dafydd R
DR
Freskos
John N
JN
Molyneaux
John M
JM
Benson
Alan G
AG
Blevis-Bal
Rhadika M
RM
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
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