Discovery of Potent and Orally Bioavailable Inverse Agonists of the Retinoic Acid Receptor-Related Orphan Receptor C2

  • ACS Med Chem Lett. 2019 May 29;10(6):972-977. doi: 10.1021/acsmedchemlett.9b00158.
Stefan von Berg  1 ,  Yafeng Xue  2 ,  Mia Collins  1 ,  Antonio Llinas  1 ,  Roine I Olsson  1 ,  Torbjörn Halvarsson  1 ,  Maria Lindskog  1 ,  Jesper Malmberg  1 ,  Johan Jirholt  1 ,  Nina Krutrök  1 ,  Marie Ramnegård  1 ,  Marie Brännström  1 ,  Anders Lundqvist  1 ,  Matti Lepistö  1 ,  Anna Aagaard  2 ,  Jane McPheat  2 ,  Eva L Hansson  2 ,  Rongfeng Chen  3 ,  Yao Xiong  3 ,  Thomas G Hansson  1 ,  Frank Narjes  1
Affiliations
  • 1. Medicinal Chemistry, DMPK, andBioscience, Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, SE-43183 Mölndal, Sweden.
  • 2. Structure, Biophysics & FBLG and Mechanistic Biology and Profiling, Discovery Sciences, R&D, AstraZeneca, Gothenburg, SE-43183 Mölndal, Sweden.
  • 3. Pharmaron Beijing Co., Ltd., Taihe Road BDA, Beijing 100176, P. R. China.
PMID: 31223457 DOI: 10.1021/acsmedchemlett.9b00158
Abstract

The further optimization of a recently disclosed series of inverse agonists of the nuclear receptor RORC2 is described. Investigations into the left-hand side of compound 1, guided by X-ray crystal structures, led to the substitution of the 4-aryl-thiophenyl residue with the hexafluoro-2-phenyl-propan-2-ol moiety. This change resulted in to compound 28, which combined improved drug-like properties with good cell potency and a significantly lower dose, using an early dose to man prediction. Target engagement in vivo was demonstrated in the thymus of mice by a reduction in the number of double positive T cells after oral dosing.

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