2. Academic Validation
  3. Discovery of Potent and Orally Bioavailable Inverse Agonists of the Retinoic Acid Receptor-Related Orphan Receptor C2

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

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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