Beyond U0126. Dianion chemistry leading to the rapid synthesis of a series of potent MEK inhibitors

Employing phenylmalonitrile dianion chemistry, a large number of analogues of MEK inhibitor lead SH053 (IC 50=140 nM) were rapidly synthesized leading to single digit nM inhibitors, displaying submicromolar AP-1 transcription inhibition in COS-7 cells. Compound 41, exhibiting a MEK IC 50=12 nM showe...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2004-03, Vol.14 (6), p.1483-1486
Hauptverfasser:	Wityak, John, Hobbs, Frank W., Gardner, Daniel S., Santella, Joseph B., Petraitis, Joseph J., Sun, Jung-Hui, Favata, Margaret F., Daulerio, Andrea J., Horiuchi, Kurumi Y., Copeland, Robert A., Scherle, Peggy A., Jaffe, Bruce D., Trzaskos, James M., Magolda, Ronald L., Trainor, George L., Duncia, John V.
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Butadienes - chemical synthesis Cercopithecus aethiops Chemistry, Pharmaceutical - methods COS Cells Enzyme Inhibitors - chemical synthesis Medical sciences Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors Mitogen-Activated Protein Kinase Kinases - metabolism Nitriles - chemical synthesis Pharmacology. Drug treatments Structure-Activity Relationship
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	Employing phenylmalonitrile dianion chemistry, a large number of analogues of MEK inhibitor lead SH053 (IC 50=140 nM) were rapidly synthesized leading to single digit nM inhibitors, displaying submicromolar AP-1 transcription inhibition in COS-7 cells. Compound 41, exhibiting a MEK IC 50=12 nM showed ip activity in a TPA-induced ear edema model with an ED 50=5 mg/kg. Graphic
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2004.01.012