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

doi:10.1016/j.bmc.2013.12.021

. 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

Yonghui Wang¹, Wei Cai², Guifeng Zhang², Ting Yang², Qian Liu², Yaobang Cheng², Ling Zhou², Yingli Ma², Ziqiang Cheng², Sijie Lu², Yong-Gang Zhao², Wei Zhang², Zhijun Xiang², Shuai Wang², Liuqing Yang², Qianqian Wu², Lisa A Orband-Miller³, Yan Xu², Jing Zhang², Ruina Gao², Melanie Huxdorf², Jia-Ning Xiang², Zhong Zhong², John D Elliott², Stewart Leung², Xichen Lin²

Affiliations

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.

PMID: 24388993
DOI: 10.1016/j.bmc.2013.12.021

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

Yonghui Wang et al. Bioorg Med Chem. 2014.

. 2014 Jan 15;22(2):692-702.

doi: 10.1016/j.bmc.2013.12.021. Epub 2013 Dec 21.

Authors

Affiliations

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.

PMID: 24388993
DOI: 10.1016/j.bmc.2013.12.021

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.

PubMed Disclaimer

Cited by

The role of retinoic acid receptor-related orphan receptors in skeletal diseases.
Zhang Y, Ma J, Bao X, Hu M, Wei X. Zhang Y, et al. Front Endocrinol (Lausanne). 2023 Nov 8;14:1302736. doi: 10.3389/fendo.2023.1302736. eCollection 2023. Front Endocrinol (Lausanne). 2023. PMID: 38027103 Free PMC article. Review.
Small molecule inhibitors of RORγt for Th17 regulation in inflammatory and autoimmune diseases.
Zeng J, Li M, Zhao Q, Chen M, Zhao L, Wei S, Yang H, Zhao Y, Wang A, Shen J, Du F, Chen Y, Deng S, Wang F, Zhang Z, Li Z, Wang T, Wang S, Xiao Z, Wu X. Zeng J, et al. J Pharm Anal. 2023 Jun;13(6):545-562. doi: 10.1016/j.jpha.2023.05.009. Epub 2023 May 20. J Pharm Anal. 2023. PMID: 37440911 Free PMC article. Review.
Discovery, Synthesis, and In Vitro Characterization of 2,3 Derivatives of 4,5,6,7-Tetrahydro-Benzothiophene as Potent Modulators of Retinoic Acid Receptor-Related Orphan Receptor γt.
Fouda A, Negi S, Zaremba O, Gaidar RS, Moroz YS, Rusanov E, Paraskevas S, Tchervenkov J. Fouda A, et al. J Med Chem. 2023 Jun 8;66(11):7355-7373. doi: 10.1021/acs.jmedchem.3c00021. Epub 2023 May 12. J Med Chem. 2023. PMID: 37172324 Free PMC article.
Journey on VX-809-Based Hybrid Derivatives towards Drug-like F508del-CFTR Correctors: From Molecular Modeling to Chemical Synthesis and Biological Assays.
Parodi A, Righetti G, Pesce E, Salis A, Tomati V, Pastorino C, Tasso B, Benvenuti M, Damonte G, Pedemonte N, Cichero E, Millo E. Parodi A, et al. Pharmaceuticals (Basel). 2022 Feb 23;15(3):274. doi: 10.3390/ph15030274. Pharmaceuticals (Basel). 2022. PMID: 35337072 Free PMC article.
Identification of potent RORβ modulators: Scaffold variation.
Doebelin C, Patouret R, Garcia-Ordonez RD, Chang MR, Dharmarajan V, Novick S, Ciesla A, Campbell S, Solt LA, Griffin PR, Kamenecka TM. Doebelin C, et al. Bioorg Med Chem Lett. 2018 Oct 15;28(19):3210-3215. doi: 10.1016/j.bmcl.2018.08.017. Epub 2018 Aug 16. Bioorg Med Chem Lett. 2018. PMID: 30143422 Free PMC article.

See all "Cited by" articles

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
- Elsevier Science
Other Literature Sources
- The Lens - Patent Citations Database
- scite Smart Citations
Chemical Information
- BindingDB
Medical
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Similar articles

Cited by

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Chemical Information

Medical

Miscellaneous

Abstract

Similar articles

Cited by

MeSH terms

Substances

Related information

LinkOut - more resources

Full Text Sources

Other Literature Sources

Chemical Information

Medical

Miscellaneous