Novel selective anti-androgens with a diphenylpentane skeleton

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Structural Biology

Background:

• Multi-template drug discovery leverages protein fold similarities to generate lead compounds.
• Polypharmacological lead compounds often require modification for target selectivity.
• Diphenylpentane compounds previously showed both anti-androgen and vitamin D activities.

Purpose of the Study:

• To separate anti-androgen and vitamin D activities of diphenylpentane lead compounds.
• To develop target-selective compounds from existing multi-template derived leads.
• To enhance anti-androgen potency and selectivity.

Main Methods:

• Utilized X-ray crystal structures of androgen receptor and vitamin D receptor.
• Introduced bulky substituents to the t-butyl group of lead compounds 2 and 3.
• Synthesized and evaluated novel diphenylpentane derivatives for biological activity.

Main Results:

• Compound 16c was synthesized, demonstrating potent anti-androgen activity (IC50: 0.13 μM).
• Compound 16c exhibited significantly higher potency than bicalutamide (IC50: 0.67 μM).
• 16c showed 30-fold selectivity for anti-androgen activity over vitamin D activity.

Conclusions:

• The multi-template approach enables the generation of lead compounds that can be structurally modified for target selectivity.
• Bulky substituent introduction based on receptor structure is an effective strategy for activity separation.
• Compound 16c represents a promising selective anti-androgen candidate for further development.