Pharmacy College, Henan University of Chinese Medicine, 450046, Zhengzhou, China.
Children's Hospital Affiliated of Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Henan, Zhengzhou, 450000, China.
Eur J Med Chem. 2024 Dec 5;279:116842. doi: 10.1016/j.ejmech.2024.116842. Epub 2024 Sep 6.
Drug candidates with poor solubility have been recognized as the cause of many drug development failures, owing to the fact that low solubility is unfavorable for physicochemical, pharmacokinetic (PK) and pharmacodynamic (PD) properties. Given the imperative role of solubility during drug development, we herein summarize various strategies for solubility optimizations from a medicinal chemistry perspective, including introduction of polar group, salt formation, structural simplification, disruption of molecular planarity and symmetry, optimizations on the solvent exposed region as well as prodrug design. In addition, methods for solubility assessment and prediction are reviewed. Besides, we have deeply discussed the strategies for solubility improvement. This paper is expected to be beneficial for the development of drug-like molecules with good solubility.
候选药物的溶解度差已被认为是导致许多药物开发失败的原因，因为低溶解度不利于理化性质、药代动力学（PK）和药效动力学（PD）特性。鉴于溶解度在药物开发过程中的重要作用，我们从药物化学的角度总结了各种提高溶解度的策略，包括引入极性基团、成盐、结构简化、破坏分子的平面性和对称性、对溶剂暴露区域的优化以及前药设计。此外，还回顾了溶解度评估和预测的方法。此外，我们还深入讨论了提高溶解度的策略。本文有望为开发具有良好溶解度的类药性分子提供帮助。
