Hit-to-lead studies: the discovery of potent, orally active, thiophenecarboxamide IKK-2 inhibitors

Andrew Baxter; Steve Brough; Anne Cooper; Eike Floettmann; Steve Foster; Christine Harding; Jason Kettle; Tom McInally; Craig Martin; Michelle Mobbs; Maurice Needham; Pete Newham; Stuart Paine; Steve St-Gallay; Sylvia Salter; John Unitt; Yafeng Xue

doi:10.1016/j.bmcl.2004.03.058

Hit-to-lead studies: the discovery of potent, orally active, thiophenecarboxamide IKK-2 inhibitors

Bioorg Med Chem Lett. 2004 Jun 7;14(11):2817-22. doi: 10.1016/j.bmcl.2004.03.058.

Authors

Andrew Baxter¹, Steve Brough, Anne Cooper, Eike Floettmann, Steve Foster, Christine Harding, Jason Kettle, Tom McInally, Craig Martin, Michelle Mobbs, Maurice Needham, Pete Newham, Stuart Paine, Steve St-Gallay, Sylvia Salter, John Unitt, Yafeng Xue

Affiliation

¹ AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH, UK. [email protected]

PMID: 15125939
DOI: 10.1016/j.bmcl.2004.03.058

Abstract

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.

MeSH terms

Administration, Oral
Amides / chemical synthesis
Amides / pharmacology*
Animals
Binding Sites
Cell Line
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology
Humans
I-kappa B Kinase
Inhibitory Concentration 50
Ligands
Models, Molecular
Protein Array Analysis
Protein Binding
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Rats
Structure-Activity Relationship
Thiophenes / chemical synthesis
Thiophenes / pharmacology

Substances

Amides
Enzyme Inhibitors
Ligands
Thiophenes
Protein Serine-Threonine Kinases
CHUK protein, human
I-kappa B Kinase
IKBKB protein, human
IKBKE protein, human