Identification, synthesis and SAR of amino substituted pyrido[3,2b]pyrazinones as potent and selective PDE5 inhibitors.
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.
Owen
Dafydd R
DR
Department of Chemistry, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK.
Walker
John K
JK
Jon Jacobsen
E
E
Freskos
John N
JN
Hughes
Robert O
RO
Brown
David L
DL
Bell
Andrew S
AS
Brown
David G
DG
Phillips
Christopher
C
Mischke
Brent V
BV
Molyneaux
John M
JM
Fobian
Yvette M
YM
Heasley
Steve E
SE
Moon
Joseph B
JB
Stallings
William C
WC
Joseph Rogier
D
D
Fox
David N A
DN
Palmer
Michael J
MJ
Ringer
Tracy
T
Rodriquez-Lens
Margarita
M
Cubbage
Jerry W
JW
Blevis-Bal
Radhika M
RM
Benson
Alan G
AG
Acker
Brad A
BA
Maddux
Todd M
TM
Tollefson
Michael B
MB
Bond
Brian R
BR
Macinnes
Alan
A
Yu
Yung
Y
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
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