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