Structure-property Relationships Reported for the New Drugs Approved in 2025

This review summarizes the structure-property relationships underlying 10 smallmolecule drugs approved by the US FDA in 2025, with an emphasis on the lead optimization strategies that facilitated their successful clinical advancement. Analysis of pharmacological and physicochemical datasets revealed two recurrent optimization approaches that effectively addressed pharmacokinetic and toxicological liabilities during development. First, the deliberate incorporation or modification of heterocyclic motifs enables the simultaneous optimization of multiple drug-like properties. Representative examples include the N-methylpyrazole substituent in aficamten, which improves oral bioavailability; substitution of a metabolically labile carbamate with a pyrimidine ring in avutometinib; and introduction of a methylated oxazolidinone moiety in zoliflodacin, which markedly increases aqueous solubility. Second, precise control of the hydrogen-bond donor count was essential for optimizing membrane permeability and oral absorption. This was achieved either through N-methylation, as demonstrated by aficamten and vimseltinib, or through intramolecular hydrogen bonding via strategically positioned acceptor groups. In several cases, fluorine substitution adjacent to NH functionalities effectively masked donor characteristics, thereby improving permeability and overall pharmacokinetic performance. Collectively, these case studies underscore the value of rigorous structure-property relationship analysis integrated with established medicinal chemistry principles. Such approaches enable the successful navigation of complex lead-to-candidate optimization challenges and provide practical guidance for future small-molecule drug discovery efforts.