Small molecule biaryl FSH receptor agonists. Part 2: Lead optimization via parallel synthesis

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Endocrinology

Background:

• The follicle-stimulating hormone (FSH) receptor plays a crucial role in reproductive health.
• Developing small molecule agonists for the FSH receptor presents therapeutic opportunities.

Purpose of the Study:

• To design, synthesize, and evaluate novel biaryl diketopiperazine compounds as FSH receptor agonists.
• To identify potent and selective agonists for potential therapeutic applications.

Main Methods:

• Preparation of three biaryl diketopiperazine optimization libraries using solid-phase parallel synthesis.
• Employing a cyclization-release method for efficient compound library generation.
• Evaluation of over 300 synthesized compounds for FSH receptor agonist activity.

Main Results:

• Discovery of potent small molecule biaryl diketopiperazine FSH receptor agonists.
• Identification of compounds 10c (EC(50)=13 nM) and 11f (EC(50)=1.2 nM) with high potency.
• Successful synthesis and evaluation of a large library of diverse compounds.

Conclusions:

• Biaryl diketopiperazines represent a promising scaffold for developing FSH receptor agonists.
• The developed synthetic methodology enables efficient exploration of chemical space for drug discovery.
• Potent agonists were identified, warranting further investigation for therapeutic potential.