Design and synthesis of nonsteroidal progesterone receptor antagonists based on C,C′-diphenylcarborane scaffold as a hydrophobic pharmacophore

• Three series of C,C′-diphenylcarborane derivatives were synthesized.
• 1,7-Diphenyl-m-carborane substructure was versatile scaffold of PR antagonist.
• Compound 39 exhibited potent PR antagonistic activity with an IC50 value of 29 nM.
• m-Carborane derivatives exhibited PR selectivity over other steroid receptors.
• Docking simulation suggested mechanism of antagonism.

The progesterone receptor (PR) plays important roles in multiple physiological processes, including female reproduction. Here, we report the synthesis of nonsteroidal PR antagonists containing a boron cluster as the hydrophobic core. We found that 1,7-diphenyl-meta-carborane was the preferred substructure among the three carborane isomers. Compound 39 was the most potent PR antagonist (IC50: 29 nM). Compound 41 also exhibited potent activity (IC50: 93 nM), and did not bind to androgen receptor, glucocorticoid receptor or mineralocorticoid receptor. These compounds may be useful for investigating potential clinical applications of PR modulators.

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