Structure-Property Relationships Reported for the New Drugs Approved in 2024

This mini-review summarizes the structure-property relationships of seven smallmolecule drugs approved in 2024, providing insights into effective lead-to-candidate optimization strategies. The analysis focused on aprocitentan, flurpiridaz F-18, inavolisib, vorasidenib, ensitrelvir, golidocitinib, and zorifertinib, highlighting the key structural modifications that enhanced their drug-like properties. Notable optimization strategies included the strategic use of five- and sixmembered nitrogen-containing heterocycles as cyclic bioisosteres and solubilizing groups. For the kinase inhibitor golidocitinib, the unique position of a solubilizing group within the binding pocket achieved dual benefits, i.e., enhanced target selectivity and physicochemical properties. When developing central nervous system-penetrant drugs such as zorifertinib, careful control of rotatable bonds, hydrogen bond donors, and molecular lipophilicity was critical for optimizing blood-brain barrier penetration while remaining suitable for oral administration. These findings on structureproperty relationships offer valuable guidance for future drug development, particularly in addressing challenges related to solubility, bioavailability, and tissue-specific drug distribution.