Acidic and basic drugs in medicinal chemistry: a perspective.

Area of Science:

• Medicinal Chemistry
• Drug Design
• Pharmacology

Background:

• Molecular acid/base properties are fundamental to drug action.
• These properties are often considered late in drug design, only if specific ionization states are required for activity.
• Medicinal chemistry programs frequently reduce basicity to avoid issues like poor selectivity or safety risks (e.g., hERG channel interactions, phospholipidosis).

Purpose of the Study:

• To review the potential benefits and drawbacks of acidic and basic drugs.
• To analyze the strategic importance of considering compound pKa values prospectively in drug design.
• To provide new insights based on recent public data regarding acid/base properties in drug development.

Main Methods:

• Literature review of acidic and basic drug properties.
• Analysis of recently available public datasets.
• Exploration of strategic implications for medicinal chemistry design hypotheses.

Main Results:

• Acid/base properties significantly influence drug efficacy and safety.
• Attenuating basicity is common but may not be the optimal strategy.
• Prospective exploration of pKa values can enhance drug design strategies.

Conclusions:

• A deeper understanding and prospective consideration of molecular pKa are vital for successful drug design.
• Balancing the advantages and disadvantages of acidic and basic compounds is key to optimizing drug candidates.
• Future drug design should integrate pKa profiling as a core element of the chemistry strategy.