Comparative Hydrophobicity, Solubility, and Metabolic Stability of 4(1<i>H</i>)-Pyridones, 4(1<i>H</i>)-Quinolones, and 9(10<i>H</i>)-Acridones

The relatively polar 4(1<i>H</i>)-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(1<i>H</i>)-quinolones (4-quinolones), and 9(10<i>H</i>)-acridones (9-acridones), measured chromatographic log <i>D</i> _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 <i>D</i>. The gain in metabolic stability was not as great for those 4-pyridone/4-quinolone pairs featuring additional polar functional groups/heterocycles.