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. 2019 May 29;10(6):972-977.
doi: 10.1021/acsmedchemlett.9b00158. eCollection 2019 Jun 13.

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

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

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

Stefan von Berg et al. ACS Med Chem Lett. .

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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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Overlay of 1 (1.84 Å, PDB: 6ESN, carbons in cyan) and HTS hit 2 (2.1 Å, PDB: 6R7A carbons in orange) in the RORC2 LBD.
Figure 2
Figure 2
Overlay of 1 (1.84 Å, PDB: 6ESN, carbons in cyan), 14 (1.8 Å, PDB: 6R7J, carbons in green), and 22 (1.5 Å, PDB: 6R7K, carbons in pink) with key interactions to the RORC2 LBD.
Figure 3
Figure 3
Effect of compounds 28 and 29 on the number of CD4+CD8+ T cells in the thymus of mice.
Scheme 1
Scheme 1. Synthesis of Analogues 14, 16, 22, 28, and 29
Reagents and conditions: (a) HATU, i-PrNEt2, CH2Cl2 85%; HCl, 1,4-dioxane, RT or TFA, CH2Cl2, quant.; (b) for 14: MeCN, AcCl, NEt3, 89%; for 16: MeCN, MeOCOCl, i-PrNEt2, 64%; for 22: PhCH2CO2H, T3P, TEA, CH2Cl2, RT, 85%; (c) SFC, 30% i-PrOH in CO2, 120 bar: 28 (41%), 29 (41%).
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