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(1 H)-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(1 H)-one, a potent and selective inhibitor...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2009-09, Vol.19 (17), p.5209-5213
Hauptverfasser:	Hughes, Robert O., Walker, John K., Joseph Rogier, D., Heasley, Steve E., Blevis-Bal, Rhadika M., Benson, Alan G., Jon Jacobsen, E., Cubbage, Jerry W., Fobian, Yvette M., Owen, Dafydd R., Freskos, John N., Molyneaux, John M., Brown, David L., Acker, Brad A., Maddux, Todd M., Tollefson, Mike B., Moon, Joseph B., Mischke, Brent V., Rumsey, Jeanne M., Zheng, Yi, MacInnes, Alan, Bond, Brian R., Yu, Ying
Format:	Artikel
Sprache:	eng
Schlagworte:	Aminopyrazinone Animals Antihypertensive agents Biological and medical sciences Cardiovascular system Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism Cyclic Nucleotide Phosphodiesterases, Type 6 - antagonists & inhibitors Cyclic Nucleotide Phosphodiesterases, Type 6 - metabolism Dogs Drug Discovery Humans Medical sciences PDE5 Pharmacokinetics Pharmacology. Drug treatments Phosphodiesterase 5 Inhibitors Phosphodiesterase Inhibitors - chemical synthesis Phosphodiesterase Inhibitors - chemistry Phosphodiesterase Inhibitors - pharmacokinetics Protein Isoforms - antagonists & inhibitors Protein Isoforms - metabolism Pyrazines - chemical synthesis Pyrazines - chemistry Pyrazines - pharmacokinetics Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacokinetics Rats Rats, Inbred SHR Structure-Activity Relationship Vasodilator agents. Cerebral vasodilators
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Zusammenfassung:	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(1 H)-one, a potent and selective inhibitor of PDE5 with an excellent PK profile.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2009.07.019