Comparative Hydrophobicity, Solubility, and Metabolic Stability of 4(1H)-Pyridones, 4(1H)-Quinolones, and...

The relatively polar 4(1H)-pyridone (4-pyridone) heterocycle is found in many drugs and drug candidates. In a comparison of the hydrophobicity, aqueous solubility, and metabolic stability of several matched sets of 4-pyridones, 4(1H)-quinolones (4-quinolones), and 9(10H)-acridones (9-acridones), measured chromatographic log D _7.4 values show that 9-acridones are more hydrophobic and less soluble than their 4-quinolone and 4-pyridone counterparts. All 4-pyridone/4-quinolone pairs had identical or very similar hydrophobicity and aqueous solubility properties. Metabolic stability increased steadily from 9-acridones to 4-quinolones to 4-pyridones, consistent with the progressive increase in Fsp³ values and log D. The gain in metabolic stability was not as great for those 4-pyridone/4-quinolone pairs featuring additional polar functional groups/heterocycles.