AZD0284, a Potent, Selective, and Orally Bioavailable Inverse Agonist of Retinoic Acid Receptor-Related Orphan Receptor C2

J Med Chem. 2021 Sep 23;64(18):13807-13829. doi: 10.1021/acs.jmedchem.1c01197.

Frank Narjes, Antonio Llinas, Stefan von Berg, Johan Jirholt, Sarah Lever, Rikard Pehrson, Mia Collins, Anna Malmberg, Petter Svanberg, Yafeng Xue ¹, Roine I Olsson, Jesper Malmberg, Glyn Hughes, Nafizal Hossain, Hanna Grindebacke, Agnes Leffler, Nina Krutrök, Elisabeth Bäck, Marie Ramnegård, Matti Lepistö, Linda Thunberg ², Anna Aagaard ¹, Jane McPheat ¹, Eva L Hansson ¹, Rongfeng Chen ³, Yao Xiong ³, Thomas G Hansson

Affiliations

1 Mechanistic & Structural Biology, Discovery Science, R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
2 Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
3 Pharmaron Beijing Co., Ltd., Taihe Road BDA, Beijing 100176, P. R. China.

PMID: 34464130 DOI: 10.1021/acs.jmedchem.1c01197

Abstract

Inverse agonists of the nuclear receptor RORC2 have been widely pursued as a potential treatment for a variety of autoimmune diseases. We have discovered a novel series of isoindoline-based inverse agonists of the nuclear receptor RORC2, derived from our recently disclosed RORC2 inverse agonist 2. Extensive structure-activity relationship (SAR) studies resulted in AZD0284 (20), which combined potent inhibition of IL-17A secretion from primary human T_H17 cells with excellent metabolic stability and good PK in preclinical species. In two preclinical in vivo studies, compound 20 reduced thymocyte numbers in mice and showed dose-dependent reduction of IL-17A containing γδ-T cells and of IL-17A and IL-22 RNA in the imiquimod induced inflammation model. Based on these data and a favorable safety profile, 20 was progressed to phase 1 clinical studies.

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