Kihang Choi

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.

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.

: Drug-like properties play pivotal roles in drug adsorption, distribution, metabolism, excretion, and toxicity. Therefore, efficiently optimizing these properties is essential for the successful development of novel therapeutics. Understanding the structure–property relationships of clinically approved drugs can provide valuable insights for drug design and optimization strategies. Among the new drugs approved in 2023, which include 31 small-molecule drugs in the US, the structure-property relationships of nine drugs were compiled from the medicinal chemistry literature, in which detailed information on pharmacokinetic and/or physicochemical properties was reported not only for the final drug but also for its key analogs generated during drug development. The structure-property relationships of nine newly approved drugs are summarized, including three kinase inhibitors and three G-protein-coupled receptor antagonists. Several optimization strategies, such as bioisosteric replacement and steric handle installation, have successfully produced clinical candidates with enhanced physicochemical and pharmacokinetic properties. The summarized structure–property relationships demonstrate how appropriate structural modifications can effectively improve overall drug-like properties. The ongoing exploration of structure– property relationships of clinically approved drugs is expected to offer valuable guidance for developing future drugs.

Background: Proteases play important roles in the regulation of many physiological processes, and protease inhibitors have become one of the important drug classes. Especially because the development of protease inhibitors often starts from a substrate- based peptidomimetic strategy, many of the initial lead compounds suffer from pharmacokinetic liabilities. Objective: To reduce drug attrition rates, drug metabolism and pharmacokinetics studies are fully integrated into modern drug discovery research, and the structure-property relationship illustrates how the modification of the chemical structure influences the pharmacokinetic and toxicological properties of drug compounds. Understanding the structure- property relationships of clinically approved protease inhibitor drugs and their analogues could provide useful information on the lead-to-candidate optimization strategies. Methods: About 70 inhibitors against human or pathogenic viral proteases have been approved until the end of 2021. In this review, 17 inhibitors are chosen for the structure- property relationship analysis because detailed pharmacological and/or physicochemical data have been disclosed in the medicinal chemistry literature for these inhibitors and their close analogues. Results: The compiled data are analyzed primarily focusing on the pharmacokinetic or toxicological deficiencies found in lead compounds and the structural modification strategies used to generate candidate compounds. Conclusion: The structure-property relationships hereby summarized how the overall druglike properties could be successfully improved by modifying the structure of protease inhibitors. These specific examples are expected to serve as useful references and guidance for developing new protease inhibitor drugs in the future.

Background: The structure–property relationship illustrates how modifying the chemical structure of a pharmaceutical compound influences its absorption, distribution, metabolism, excretion, and other related properties. Understanding structure–property relationships of clinically approved drugs could provide useful information for drug design and optimization strategies. Method: Among new drugs approved around the world in 2022, including 37 in the US, structure– property relationships of seven drugs were compiled from medicinal chemistry literature, in which detailed pharmacokinetic and/or physicochemical properties were disclosed not only for the final drug but also for its key analogues generated during drug development. Results: The discovery campaigns for these seven drugs demonstrate extensive design and optimization efforts to identify suitable candidates for clinical development. Several strategies have been successfully employed, such as attaching a solubilizing group, bioisosteric replacement, and deuterium incorporation, resulting in new compounds with enhanced physicochemical and pharmacokinetic properties. Conclusion: The structure-property relationships hereby summarized illustrate how proper structural modifications could successfully improve the overall drug-like properties. The structure–property relationships of clinically approved drugs are expected to continue to provide valuable references and guides for the development of future drugs.

Background: G-protein-coupled receptors (GPCRs) are the largest family of membrane receptors and the most intensively studied drug targets. Given the physiological importance of signal transduction by GPCRs and the recent progress in the structure determination of membrane proteins, the development of GPCR antagonists and agonists is expected to continue to be a major area of medicinal chemistry research. Methods: The structure-property relationship illustrates how the modification of the chemical structure influences the absorption, distribution, metabolism, excretion, and other related properties of drug compounds. Understanding the structure-property relationships of clinically approved GPCR-targeted drugs and their analogues could provide useful information on the lead-to-candidate optimization strategies. Results: Among more than 50 GPCR antagonists and agonists approved in the last decade, the structure-property relationships of 17 drugs are compiled from medicinal chemistry literature, in which detailed pharmacokinetic and toxicological properties are disclosed not only for the final drug candidate but also for key analogues generated during the lead optimization campaign. Conclusion: The structure-property relationships hereby summarized demonstrate how in vitro and in vivo properties of the membrane protein-targeted ligands could be effectively optimized, in many cases, without requiring a significant change in the molecular size. This information is expected to provide valuable insights to expedite new GPCR-targeted drug development.

Background: Protein kinase inhibitors have become one of the most successful classes of small-molecule drugs during the last decades. In modern drug discovery, considering ‘drug-like’ physicochemical and pharmacokinetic properties as early as possible in drug design is widely acknowledged as an important strategy to reduce drug attrition rates. Methods: In this review, clinically approved 25 protein kinase inhibitors and their key analogues reported in medicinal chemistry literature were compared for their biological, physicochemical, and pharmacokinetic properties. Although there is no common trajectory to follow through complex drug discovery campaigns, knowledge of the structure–activity relationship obtained from the successful lead optimization studies might be extended to other drug design efforts. Results: Among more than 70 protein kinase inhibitors clinically approved around the world, the structure–activity relationships of 25 inhibitors and their key analogues are compiled from medicinal chemistry literature, in which detailed results from the ‘lead-to-candidate’ stage are available with associated property data. For the other inhibitors, such information has not been disclosed in the literature, or the available data is limited and not sufficient to provide clear structural analysis. Conclusion: The structure–property relationships summarized for 25 inhibitors and their analogues illustrate general guidelines for lead optimization and candidate selection, and this information could be extended for better property-based drug design in the future.

Although many people affected by COVID-19 suffer from some form of psychological distress, access to proper treatment or psychosocial interventions has been limited. This study aimed to examine the feasibility and preliminary effects of a therapeutic gardening program conducted during the COVID-19 pandemic. The program consisted of 30 sessions and was conducted at 10 nationwide sites in Korea from June to November 2021. Mental health and well-being were assessed using the Mental Health Screening Tool for Depressive Disorders, Mental Health Screening Tool for Anxiety Disorders, Engagement in Daily Activity Scale, brief version of World Health Organization Quality of Life, and Mindful Attention Awareness Scale. Cohen’s d value was calculated for the effect size, and a multilevel analysis was used to determine the longitudinal effects of therapeutic gardening. The effect sizes for depression, anxiety, daily activities, quality of life, and mindfulness were 0.84, 0.72, 0.61, 0.64, and 0.40, respectively. Multilevel analyses showed that all five mental health variables improved significantly over time as the therapeutic gardening program progressed. Therapeutic gardening is promising and applicable as a nature-based intervention to improve the mental health of individuals experiencing psychological distress especially in the COVID-19 pandemic.

Arrhenius photobases are of potential use for excited state hydroxide ion dissociation (ESHID), photo-induced pOH jump experiments, and base-catalyzed reactions. However, previously studied Arrhenius photobases have to be excited by UV light and undergo ESHID reactions only in protic solvents. These characteristics have become a disadvantage to their application in many fields of research. In this work, we have designed and synthesized a new Arrhenius photobase (NO₂-Acr-OH), the ESHID reaction of which is readily triggered by visible light excitation. In contrast to previously studied Arrhenius photobases, NO₂-Acr-OH undergoes ESHID reactions in protic solvents as well as in polar aprotic solvents. Solvent-dependent photo-induced reactions of NO₂-Acr-OH are comprehensively studied by time-resolved fluorescence spectroscopy. Molecular designs for visible light triggered acridinol-based Arrhenius photobases with a large ΔpK_b value are proposed.

Eui Man Jeong, Ji-Woong Shin, Jisun Lim, Ju Hwan Kim, Hyewon Kang, Yingfu Yin, Hye-Mi Kim, YongHwan Kim, Sun-Gi Kim, Heun-Soo Kang, Dong-Myung Shin, Kihang Choi, In-Gyu Kim. IJSC 1999;0:. https://doi.org/10.15283/ijsc18151