Imidazo[4,5-d]thiazolo[5,4-b]pyridine based inhibitors of IKK2: synthesis, SAR, PK/PD and activity in a preclinical model of rheumatoid arthritis

Alaric J Dyckman; Charles M Langevine; Claude Quesnelle; James Kempson; Junqing Guo; Patrice Gill; Steven H Spergel; Scott H Watterson; Tianle Li; David S Nirschl; Kathleen M Gillooly; Mark A Pattoli; Kim W McIntyre; Laishun Chen; Murray McKinnon; John H Dodd; Joel C Barrish; James R Burke; William J Pitts

doi:10.1016/j.bmcl.2010.10.133

Imidazo[4,5-d]thiazolo[5,4-b]pyridine based inhibitors of IKK2: synthesis, SAR, PK/PD and activity in a preclinical model of rheumatoid arthritis

Bioorg Med Chem Lett. 2011 Jan 1;21(1):383-6. doi: 10.1016/j.bmcl.2010.10.133. Epub 2010 Oct 31.

Affiliation

¹ Bristol-Myers Squibb, Research and Development, Princeton, NJ 08543-4000, USA. alaric.dyckman@bms.com

PMID: 21087862
DOI: 10.1016/j.bmcl.2010.10.133

Abstract

The synthesis, structure-activity relationships (SAR) and biological evaluation of thiazole based tricyclic inhibitors of IKK2 are described. Compound 9 was determined to be orally efficacious in a murine model of rheumatoid arthritis.

MeSH terms

Animals
Arthritis, Rheumatoid / drug therapy*
Disease Models, Animal
Dogs
Drug Evaluation, Preclinical
Female
I-kappa B Kinase / antagonists & inhibitors*
I-kappa B Kinase / metabolism
Imidazoles / chemistry*
Mice
Mice, Inbred BALB C
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / therapeutic use
Pyridines / chemistry*
Pyridines / pharmacokinetics
Pyridines / therapeutic use
Rats
Structure-Activity Relationship
Thiazoles / chemistry*

Substances

Imidazoles
Protein Kinase Inhibitors
Pyridines
Thiazoles
imidazole
I-kappa B Kinase