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Bioorg Med Chem. 2014 Jan 15;22(2):692-702. doi: 10.1016/j.bmc.2013.12.021. Epub 2013 Dec 21.

Discovery of novel N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides as potent RORγt inhibitors.

Author information

1
Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China. Electronic address: wang.2.yonghui@gmail.com.
2
Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
3
Research and Development, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.

Abstract

Novel series of N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides were discovered as potent retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitors. SAR studies of the RORγt HTS hit 6a led to identification of thiazole ketone amide 8h and thiophene ketone amide 9g with high binding affinity and inhibitory activity of Th17 cell differentiation. Compound 8h showed in vivo efficacy in both mouse experimental autoimmune encephalomyelitis (EAE) and collagen induced arthritis (CIA) models via oral administration.

KEYWORDS:

Multiple sclerosis; RORγt inhibitor; Rheumatoid arthritis; Th17 cell differentiation

PMID:
24388993
DOI:
10.1016/j.bmc.2013.12.021
[Indexed for MEDLINE]
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