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Harcken C, Csengery J, Turner M, et al. Discovery of a Series of Pyrazinone RORγ Antagonists and Identification of the Clinical Candidate BI 730357. ACS Med Chem Lett. 2021;12(1):143-154doi: 10.1021/acsmedchemlett.0c00575.
Harcken, C., Csengery, J., Turner, M., Wu, L., Liang, S., Sibley, R., Brunette, S., Labadia, M., Hoyt, K., Wayne, A., Wieckowski, T., Davis, G., Panzenbeck, M., Souza, D., Kugler, S., Terenzio, D., Collin, D., Smith, D., Fryer, R. M., Tseng, Y. C., Hehn, J. P., Fletcher, K., & Hughes, R. O. (2021). Discovery of a Series of Pyrazinone RORγ Antagonists and Identification of the Clinical Candidate BI 730357. ACS medicinal chemistry letters, 12(1), 143-154. https://doi.org/10.1021/acsmedchemlett.0c00575
Harcken, Christian, et al. "Discovery of a Series of Pyrazinone RORγ Antagonists and Identification of the Clinical Candidate BI 730357." ACS medicinal chemistry letters vol. 12,1 (2021): 143-154. doi: https://doi.org/10.1021/acsmedchemlett.0c00575
Harcken C, Csengery J, Turner M, Wu L, Liang S, Sibley R, Brunette S, Labadia M, Hoyt K, Wayne A, Wieckowski T, Davis G, Panzenbeck M, Souza D, Kugler S, Terenzio D, Collin D, Smith D, Fryer RM, Tseng YC, Hehn JP, Fletcher K, Hughes RO. Discovery of a Series of Pyrazinone RORγ Antagonists and Identification of the Clinical Candidate BI 730357. ACS Med Chem Lett. 2021 Jan 05;12(1):143-154. doi: 10.1021/acsmedchemlett.0c00575. eCollection 2021 Jan 14. PMID: 33488976; PMCID: PMC7812678.
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ACS Med Chem Lett. 2021 Jan 05;12(1):143-154. doi: 10.1021/acsmedchemlett.0c00575. eCollection 2021 Jan 14.

Discovery of a Series of Pyrazinone RORγ Antagonists and Identification of the Clinical Candidate BI 730357.

ACS medicinal chemistry letters

Christian Harcken, Johanna Csengery, Michael Turner, Lifen Wu, Shuang Liang, Robert Sibley, Steven Brunette, Mark Labadia, Kathleen Hoyt, Anita Wayne, Thomas Wieckowski, Gregg Davis, Mark Panzenbeck, Donald Souza, Stanley Kugler, Donna Terenzio, Delphine Collin, Dustin Smith, Ryan M Fryer, Yin-Chao Tseng, Jörg P Hehn, Kim Fletcher, Robert O Hughes

Affiliations

  1. Department of R&D Project Management and Development Strategies, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States.
  2. Department of Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States.
  3. Department of Immunology and Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States.
  4. Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States.
  5. Department of Medicinal Chemistry Germany, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany.

PMID: 33488976 PMCID: PMC7812678 DOI: 10.1021/acsmedchemlett.0c00575

Abstract

The interleukin (IL)-23/T helper (Th)17 axis plays a critical role in autoimmune diseases, and there is an increasing number of biologic therapies that target IL-23 and IL-17. The transcription factor retinoic acid receptor-related orphan nuclear receptor γt (RORγt) is important for the activation and differentiation of Th17 cells and thus is an attractive pharmacologic target for the treatment of Th17-mediated diseases. A novel series of pyrazinone RORγ antagonists was discovered through hybridization of two distinct screening hits and scaffold hopping. The series offers attractive potency and selectivity in combination with favorable druglike properties, such as metabolic stability and aqueous solubility. Lead optimization identified a clinical candidate, compound (

© 2021 American Chemical Society.

Conflict of interest statement

The authors declare no competing financial interest.

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