Identification of potent RORβ modulators: Scaffold variation

Abstract

We sought to develop RORβ-selective probe molecules in order to investigate the function of the receptor in vitro and in vivo and its role in the pathophysiology of disease. To accomplish this, we modified a potent dual RORβ/RORγ inverse agonist from the primary literature with the goal of improving selectivity for RORβ vs RORγ. Truncation of the Western portion of the molecule ablated activity at RORγ and led to a potent series of RORβ modulators. Continued exploration of this series investigated alternate replacement cores for the aminothiazole ring. Numerous suitable replacements were found during the course of our SAR investigations and are reported herein.

Keywords: Aminothiophene; Nuclear receptor; RORβ; Selective ligand.

Figure 1.

Aminothiophenes as potent RORβ modulators

Figure 2:

Conformational dynamics probed by HDX of RORβ inverse agonist 1, 25-Hydroxycholesterol (25-HC), 44 and T09

Figure 3:

Gal4-LBD assay of compounds 1 and 44.

Scheme 1.

Reagents and Conditions: (a) R¹PhCOCl, AlCl₃ or SnCl₄, DCE, 40 °C; (b) R²PhB(OH)₂, Pd(Ph₃P)₄, Na₂CO₃, toluene/EtOH/H₂O 80 °C; (c) diphenylphosphorylazide, Et₃N, tBuOH, 90 °C; (d) TFA/DCM, rt, then trifluoroacetic anhydride, Et³N, DCM, 0 °C; (e) K₂CO₃, MeOH, 40 °C.