Ren Rongguo, Zhong Longjin, Noack Cassandra, Kaushik Deepender, Leas Derek A, Wang Xiaofang, Dong Yuxiang, Charman Susan A, Vennerstrom Jonathan L
College of Pharmacy, University of Nebraska Medical Center, 986125 Nebraska Medical Center, Omaha, Nebraska 68198-6025, United States.
Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
ACS Med Chem Lett. 2025 Mar 24;16(4):583-587. doi: 10.1021/acsmedchemlett.4c00618. eCollection 2025 Apr 10.
The relatively polar 4(1)-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)-quinolones (4-quinolones), and 9(10)-acridones (9-acridones), measured chromatographic log 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 Fsp values and log . The gain in metabolic stability was not as great for those 4-pyridone/4-quinolone pairs featuring additional polar functional groups/heterocycles.
相对极性的4(1)-吡啶酮（4-吡啶酮）杂环存在于许多药物及候选药物中。在对几组匹配的4-吡啶酮、4(1)-喹诺酮（4-喹诺酮）和9(10)-吖啶酮（9-吖啶酮）的疏水性、水溶性及代谢稳定性进行比较时，测得的色谱log 值表明，9-吖啶酮比其对应的4-喹诺酮和4-吡啶酮更疏水且溶解度更低。所有4-吡啶酮/4-喹诺酮对具有相同或非常相似的疏水性和水溶性特性。代谢稳定性从9-吖啶酮到4-喹诺酮再到4-吡啶酮稳步增加，这与Fsp值和log 的逐渐增加一致。对于那些具有额外极性官能团/杂环的4-吡啶酮/4-喹诺酮对，代谢稳定性的增加幅度没有那么大。
