4-Phenyl-7-azaindoles as potent, selective and bioavailable IKK2 inhibitors demonstrating good in vivo efficacy

John Liddle; Paul Bamborough; Michael D Barker; Sebastien Campos; Chun-Wa Chung; Rick P C Cousins; Paul Faulder; Michelle L Heathcote; Heather Hobbs; Duncan S Holmes; Chris Ioannou; Cesar Ramirez-Molina; Mary A Morse; Ruth Osborn; Jeremy J Payne; John M Pritchard; William L Rumsey; Daniel T Tape; Giorgia Vicentini; Caroline Whitworth; Rick A Williamson

doi:10.1016/j.bmcl.2012.06.065

4-Phenyl-7-azaindoles as potent, selective and bioavailable IKK2 inhibitors demonstrating good in vivo efficacy

Bioorg Med Chem Lett. 2012 Aug 15;22(16):5222-6. doi: 10.1016/j.bmcl.2012.06.065. Epub 2012 Jun 26.

Affiliation

¹ GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. john.2.liddle@gsk.com

PMID: 22801646
DOI: 10.1016/j.bmcl.2012.06.065

Abstract

The lead optimization of a series of potent azaindole IKK2 inhibitors is described. Optimization of the human whole blood activity and selectivity over IKK1 in parallel led to the discovery of 16, a potent and selective IKK2 inhibitor showing good efficacy in a rat model of neutrophil activation.

MeSH terms

Animals
Biological Availability
Disease Models, Animal
Half-Life
Humans
I-kappa B Kinase / antagonists & inhibitors*
I-kappa B Kinase / metabolism
Indoles / chemical synthesis
Indoles / chemistry*
Indoles / pharmacokinetics
Lung / metabolism
Neutrophils / immunology
Neutrophils / metabolism
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Rats
Structure-Activity Relationship

Substances

7-azaindole dimer
Indoles
Protein Kinase Inhibitors
I-kappa B Kinase