Pyridine containing M(1) positive allosteric modulators with reduced plasma protein binding.

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Pharmacology

Background:

• Quinolone carboxylic acids are a known scaffold for M1 positive allosteric modulators.
• High plasma protein binding can limit the central nervous system (CNS) exposure of drugs.
• Modulating M1 receptors is a therapeutic strategy for various neurological disorders.

Purpose of the Study:

• To investigate the impact of incorporating pyridine and diazine moieties into the biphenyl region of quinolone carboxylic acid derivatives.
• To reduce the plasma protein binding of these M1 positive allosteric modulators.
• To enhance the CNS exposure of potential M1 positive allosteric modulators.

Main Methods:

• Synthesis of novel quinolone carboxylic acid derivatives containing pyridine and diazine rings.
• In vitro assessment of plasma protein binding affinity.
• Evaluation of CNS penetration or exposure in relevant models.

Main Results:

• Successful incorporation of pyridines and diazines into the biphenyl core.
• Demonstrated reduction in plasma protein binding for the modified compounds compared to parent structures.
• Evidence suggesting improved CNS exposure or brain penetration.

Conclusions:

• Incorporating pyridines and diazines is a viable strategy to decrease plasma protein binding of M1 positive allosteric modulators.
• This modification holds promise for developing M1 modulators with enhanced CNS efficacy.
• Further development of these compounds could lead to novel therapeutics for CNS conditions.