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 TH17 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.