Second basic pKa: An overlooked parameter in predicting phospholipidosis-inducing potential of diamines

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Toxicology

Background:

• Phospholipidosis is a condition caused by certain drugs that accumulate in lysosomes.
• Predicting the phospholipidosis-inducing potential (PLIP) of drug candidates is crucial for safety.
• Existing prediction methods may not be suitable for fragment-sized diamines.

Purpose of the Study:

• To evaluate the PLIP of forty fragment-sized diamines.
• To investigate the relationship between PLIP and physicochemical properties.
• To identify reliable predictors for PLIP in fragment-sized diamines.

Main Methods:

• Synthesis of forty fragment-sized diamines.
• Assessment of phospholipidosis-inducing potential (PLIP).
• Calculation and analysis of physicochemical properties including ClogP and pKa values.

Main Results:

• Fragment-sized diamines derived from N-benzyl-4-(methylamino)piperidine were synthesized and tested.
• The second basic pKa was found to be a more accurate predictor of PLIP than ClogP or the most basic pKa.
• Previously reported methods were found unsuitable for predicting the PLIP of these compounds.

Conclusions:

• The second basic pKa is a key physicochemical property for predicting phospholipidosis-inducing potential in fragment-sized diamines.
• This study establishes a novel relationship between PLIP and second basic pKa.
• Accurate PLIP prediction can aid in the early identification of potential drug safety issues.