Transaminases Provide Key Chiral Building Blocks for the Synthesis of Selective M1/M4 Agonists

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Biocatalysis

Background:

• Muscarinic M4 agonists are important therapeutic targets.
• Efficient synthesis of chiral spirocyclic diamines is challenging.
• Developing selective M1/M4 agonists requires novel synthetic strategies.

Purpose of the Study:

• To develop a chiral synthetic route towards muscarinic M4 agonists.
• To utilize biocatalysis for the synthesis of key spirocyclic diamine building blocks.
• To identify selective M1/M4 agonists through medicinal chemistry efforts.

Main Methods:

• Biocatalytic synthesis of spirocyclic diamine building blocks (10 and 12).
• Optimization of a synthetic sequence using bifunctional diamine intermediates.
• Early medicinal chemistry exploration using advanced intermediates.

Main Results:

• Successful development of a chiral route to muscarinic M4 agonists.
• Efficient synthesis of key spirocyclic diamine building blocks via biocatalysis.
• Identification of selective M1/M4 agonists.

Conclusions:

• The developed chiral route, enabled by biocatalysis, is effective for synthesizing muscarinic M4 agonists.
• Bifunctional spirocyclic diamines are valuable intermediates for medicinal chemistry.
• This approach facilitates the discovery of selective M1/M4 agonists.