3,5-Disubstituted-indole-7-carboxamides: the discovery of a novel series of potent, selective inhibitors of IKK-β

David D Miller; Paul Bamborough; John A Christopher; Ian R Baldwin; Aurelie C Champigny; Geoffrey J Cutler; Jeffrey K Kerns; Timothy Longstaff; Geoffrey W Mellor; James V Morey; Mary A Morse; Hong Nie; William L Rumsey; John J Taggart

doi:10.1016/j.bmcl.2011.02.107

3,5-Disubstituted-indole-7-carboxamides: the discovery of a novel series of potent, selective inhibitors of IKK-β

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2255-8. doi: 10.1016/j.bmcl.2011.02.107. Epub 2011 Mar 1.

Authors

David D Miller¹, Paul Bamborough, John A Christopher, Ian R Baldwin, Aurelie C Champigny, Geoffrey J Cutler, Jeffrey K Kerns, Timothy Longstaff, Geoffrey W Mellor, James V Morey, Mary A Morse, Hong Nie, William L Rumsey, John J Taggart

Affiliation

¹ GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.

PMID: 21429745
DOI: 10.1016/j.bmcl.2011.02.107

Abstract

The discovery and hit-to-lead exploration of a novel series of selective IKK-β kinase inhibitors is described. The initial lead fragment 3 was identified by pharmacophore-directed virtual screening. Homology model-driven SAR exploration of the template led to potent inhibitors, such as 12, which demonstrate efficacy in cellular assays and possess encouraging developability profiles.

MeSH terms

Administration, Oral
Amides / chemical synthesis
Amides / chemistry*
Amides / pharmacokinetics
Animals
Binding Sites
Computer Simulation
Drug Evaluation, Preclinical
Humans
I-kappa B Kinase / antagonists & inhibitors*
I-kappa B Kinase / metabolism
Indoles / chemistry*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Rats
Structure-Activity Relationship

Substances

Amides
Indoles
Protein Kinase Inhibitors
indole
I-kappa B Kinase