Adaptation of the Mitsunobu Reaction for Facile Synthesis of Dorsomorphin-Based Library

Area of Science:

• Medicinal Chemistry
• Drug Design
• Biochemistry

Background:

• Pyrazolo[1,5-a]pyrimidine scaffolds mimic adenine, making them valuable in developing ATP-competitive kinase inhibitors.
• Dorsomorphin, a known AMPK inhibitor, exhibits limited kinase selectivity due to conserved ATP-binding pockets.
• Optimizing side substituents on common scaffolds is critical for achieving target selectivity in drug development.

Purpose of the Study:

• To develop and implement a convergent synthesis strategy for dorsomorphin and its analogs.
• To create a diverse series of compounds for assessing biological activity against AMPK.
• To establish an efficient route for generating targeted libraries of kinase inhibitors and receptor ligands.

Main Methods:

• Convergent synthesis strategy for dorsomorphin and close analogs.
• Mitsunobu reaction for synthesizing variants of the phenoxy-alkylamine moiety.
• Biological activity assessment towards AMPK.

Main Results:

• Successful implementation of a novel convergent synthesis for dorsomorphin analogs.
• Generation of a small, highly diversified compound series.
• Demonstrated utility of the Mitsunobu reaction for creating diverse phenoxy-alkylamine moieties.

Conclusions:

• The developed synthesis strategy provides a versatile platform for creating analogs of dorsomorphin.
• This approach facilitates the generation of focused libraries for discovering selective ATP-competitive kinase inhibitors.
• The methodology is applicable to developing potent ligands for various receptors.