Atropisomerism in the Pharmaceutically Relevant Realm

Area of Science:

• Medicinal Chemistry
• Organic Chemistry
• Stereochemistry

Background:

• Atropisomerism, a type of conformational chirality arising from hindered rotation around a single bond, is found in various pharmaceutically relevant molecular scaffolds.
• Atropisomers are classified into three stability classes (1, 2, and 3) based on their racemization half-life at 37 °C, with Class 3 isomers generally considered suitable for drug development.
• While Class 1 atropisomers are less stable, they can still adopt specific chiral conformations that influence target binding.

Purpose of the Study:

• To explore the application of atropisomerism as a design strategy to improve the target selectivity of drug candidates.
• To investigate the role of conformational preorganization around atropisomeric axes in achieving enhanced target selectivity.
• To review recent advancements in atroposelective synthesis methodologies for pharmaceutically relevant scaffolds.

Main Methods:

• Leveraging atropisomerism in medicinal chemistry to enhance selectivity of promiscuous lead compounds, initially focusing on Class 3 atropisomers in kinase inhibitors.
• Analyzing binding conformations of ligands to understand the impact of dihedral angles around prospective atropisomeric axes on target interactions.
• Developing and applying catalytic atroposelective methodologies for the synthesis of enantiomerically pure atropisomers, particularly for heterobiaryl and diarylamine scaffolds.

Main Results:

• Demonstrated proof-of-principle that different atropisomers can exhibit distinct selectivity profiles, leading to improved target selectivity.
• Established that preorganizing the atropisomeric axis into a preferred conformation for a target can significantly increase selectivity.
• Contributed to the development of atroposelective synthetic strategies for privileged pharmaceutical scaffolds.

Conclusions:

• Atropisomerism has evolved from a potential liability to a valuable tool for modulating the properties of biologically active molecules in drug discovery.
• Understanding the conformational effects of atropisomeric axes on target binding is crucial for designing selective drugs.
• Advances in atroposelective synthesis are essential for accessing pure atropisomers required for pharmaceutical applications.