Hit-to-lead studies: the discovery of potent, orally active, thiophenecarboxamide IKK-2 inhibitors.
A hit-to-lead optimisation programme was carried out on the thiophenecarboxamide high throughput screening hits 1 and 2 resulting in the discovery of the potent and orally bioavailable IKK-2 inhibitor 22.
Baxter
Andrew
A
AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH, UK. andrew.jg.baxter@astrazeneca.com
Brough
Steve
S
Cooper
Anne
A
Floettmann
Eike
E
Foster
Steve
S
Harding
Christine
C
Kettle
Jason
J
McInally
Tom
T
Martin
Craig
C
Mobbs
Michelle
M
Needham
Maurice
M
Newham
Pete
P
Paine
Stuart
S
St-Gallay
Steve
S
Salter
Sylvia
S
Unitt
John
J
Xue
Yafeng
Y
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D040081:Protein Array Analysis; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology
D000577:Amides; D004791:Enzyme Inhibitors; D008024:Ligands; D013876:Thiophenes; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human