Medicinal Research Reviews

Umair, Muhammad; Ferron, Laurent; Ali, Raja Hussain; Zamponi, Gerald W.; Tamboli, Yasinalli

doi: 10.1002/med.70068pmid: 42272247

Voltage‐gated ion channels play important physiological roles by regulating the electrical activity of a range of different cell types through maintaining the gradients of different ions. Among these, voltage‐gated calcium channels mediate various cellular activities, including muscle contraction, gene regulation, and neurotransmission. A sub‐type of calcium channels are T‐type calcium channels that play a critical role in regulating neuronal excitability and are essential for neurodevelopment. Mutations in genes encoding T‐type calcium channels, including CACNA1G, CACNA1H, and CACNA1I can lead to altered channel activity, resulting in disrupted calcium entry, calcium signaling, synaptic plasticity, and neuronal differentiation. They have been implicated in a range of neurodevelopmental disorders, such as epilepsy, autism spectrum disorder, and intellectual disability. There has been considerable interest in developing blockers against T‐type calcium channels to restore the dysregulated calcium homeostasis in neuronal disorders. T‐type calcium channel blockers, originally developed for cardiovascular diseases, have emerged as potential therapeutic agents for neurodevelopmental disorders by targeting aberrant calcium signaling. This review explores the molecular mechanisms underlying T‐type channel dysfunction caused by genetic mutations and evaluates the current evidence on the therapeutic efficacy of T‐type calcium channel blockers in neurodevelopmental disorders. Although preclinical studies show promise, translating these findings into effective clinical therapies presents significant challenges. Future research focusing on optimizing blocker specificity and understanding the broader impact of channel modulation is necessary for developing targeted treatments for neurological pathologies.

Sleebs, Brad E.

doi: 10.1002/med.70065pmid: 42227058

Malaria is a devastating disease caused by Plasmodium parasites. Plasmodium parasites express ten cathepsin D‐like aspartyl proteases, called plasmepsins (PMs). These PMs have diverse roles fulfill diverse functions throughout the parasite's lifecycle, though several exhibit functional redundancies. Among them, PMV, PMIV, and PMX are essential for asexual stage development, positioning them as prime candidates for antimalarial development. This review synthesizes current knowledge on PM biology and highlights the pivotal role of PM inhibitors in validating these proteases as therapeutic targets. Learnings from past research on PMs coupled with advances in experimental approaches have largely steered drug discovery efforts toward the development of dual PMIX/PMX inhibitors. Highlighted is an overview of the developmental trajectory of PM inhibitors, their progress to date, and their potential integration into future antimalarial therapies aimed at both prevention and treatment.

Zhang, Dashuai; Cao, Shugeng; He, Shan; Mao, Shengjun; Luo, Sulan; Ding, Lijian

doi: 10.1002/med.70067pmid: 42277622

Ion channels represent a significant class of drug targets implicated in the development of various diseases. In recent years, there has been a significant increase in research on the structure and function of ion channels, thereby promoting the study of drug targeting mechanisms involving these channels. The ocean serves as a rich reservoir of lead compounds for drug development, undeniably providing a valuable source for ion channel‐targeting drugs. However, various factors contribute to the superficial nature of many studies on drug action mechanisms and there is ongoing confusion surrounding related concepts. This review systematically reviews the mechanisms of action of marine natural products and synthetic derivatives studied from 2000 to 2025, with the goal to establish reference standards relevant to this field of study. Additionally, we systematically review the structure‐activity relationship studies and summarize drug optimization strategies in subsequent sections. The primary objective of this review is to promote deeper investigations into drug action mechanisms, providing insights for drug development and fostering the emergence of more precise pharmacological terminology to clarify these complex mechanisms.

Ren, Shufan; Wang, Kai; Wang, Jialiang; Xie, Jiatong; Zhou, Jiayi; Hou, Wenjie; Tong, Ruiqing; Hu, Qinghua; Li, Huanqiu

doi: 10.1002/med.70066pmid: 42246150

The P2Y14 receptor (P2Y14R) is a G protein‐coupled receptor (GPCR) that can be activated by the extracellular nucleotide uridine diphosphate glucose (UDPG). It performs crucial regulatory roles in diverse pathophysiological contexts, such as immune modulation, inflammatory responses, tumor progression, and metabolic disorders. Therefore, it represents a highly attractive therapeutic target. This review elucidates the signal transduction mechanism of P2Y14R and its pathological functions in conditions such as gouty arthritis (GA) and neuropathic pain (NP). Meanwhile, P2Y14R inhibitors based on multiple drug discovery strategies are also comprehensively summarized. Furthermore, this review analyzes the key challenges currently faced in inhibitors research and development. By integrating the latest reported crystal structure of P2Y14R, it looks forward to the prospects of precise drug design based on structure and clinical translation. This provides a theoretical basis and innovative direction for the future development of P2Y14R‐targeted therapeutic drugs.

Liu, Hua; Ma, Feihai; Wang, Zexu; Li, Zhiyu; Bian, Jinlei; Yuan, Zeli; Wu, Tizhi

doi: 10.1002/med.70069pmid: 42246396

Signal transducer and activator of transcription 6 (STAT6) is a key transcription factor in cytokine signaling, serving as the central effector of the IL‐4 and IL‐13 pathways. STAT6 orchestrates a range of physiological and pathological processes, including immune homeostasis and tumor development, making it an attractive therapeutic target for Th2‐driven diseases and certain cancers. While the development of STAT6‐directed agents remains at an early stage, the rapid clinical progression of the highly selective degrader KT‐621 has revitalized interest in this target. In this review, we systematically summarize recent advances in STAT6 inhibitors and degraders, with a focus on structural features, design strategies, and biological evaluation. We also highlight current challenges and future opportunities, aiming to provide useful guidance for the discovery and optimization of next‐generation STAT6‐directed therapeutics.

Mou, Guo‐Liang; Dai, Tian‐Li; Zhang, Bao‐Qi; Luo, Xiong‐Fei; Gao, Gui‐Ping; Li, Quan‐Ke; Pan, Zhong‐Qi; Zhang, Shao‐Yong; Zhang, Zhi‐Jun; Liu, Ying‐Qian

doi: 10.1002/med.70072pmid: 42299746

Castellino, Irene; Bartolini, Manuela; Andrys, Rudolf; Musilek, Kamil

doi: 10.1002/med.70071pmid: 42294559

The circadian clock mechanism generates 24‐h rhythms crucial for regulating various physiological processes, and its dysregulation has been implicated in numerous diseases. In cells, the circadian clock operates through a transcriptional‐translational feedback loop, where phosphorylation plays a pivotal role in maintaining accurate circadian rhythms. Consequently, kinase inhibitors have emerged as promising targets for modulating the circadian clock and potentially treating circadian‐related diseases. This review aims to provide an overview of the current state‐of‐the‐art of kinase inhibitors with effects on the mammalian circadian clock. By highlighting promising targets and addressing the limitations of existing inhibitors, this review intends to provide a guide for future research efforts towards the development of novel compounds for the treatment of circadian‐related disorders. Furthermore, it highlights the critical discrepancy between in vitro activity and in vivo effectiveness, emphasizing the critical need for rigorous in vivo validation to translate the therapeutic potential of kinase inhibitors into effective treatments for these disorders.

Gangwal, Amit; Lavecchia, Antonio

doi: 10.1002/med.70074pmid: 42310963

Artificial intelligence (AI) is transforming synthetic chemistry from task‐specific predictors into integrated platforms that unify retrosynthesis, reaction optimization, and closed‐loop robotic automation. This review highlights how AI‐assisted planning and robotic execution shorten cycle times, reduce step counts, and improve route sustainability in medicinal chemistry. Recent advances, including large language models (LLMs), template‐free retrosynthesis, and Bayesian optimization, are evaluated alongside key limitations in dataset quality, reproducibility, and deployment costs. To ensure translational relevance, reproducible benchmarks such as step count, time‐to‐in vitro, and green metrics (E‐factor, process mass intensity) are emphasized. This review proposes a hierarchical framework structured across three interconnected levels: cognitive planning, physical execution, and translational evaluation. Within this structure, key elements include LLM‐based synthesis planning, robotic and closed‐loop execution, interpretable decision‐making, sustainability‐by‐design, advanced reaction optimization, and multi‐objective retrosynthesis. Together, these components provide a conceptual basis for integrating digital intelligence with physical experimentation. By embedding green chemistry principles and regulatory awareness, AI is increasingly positioned not only as a predictive tool but also as an assistive collaborator supporting decision‐making in medicinal chemistry workflows. The convergence of AI, robotics, and sustainability metrics highlights an emerging transition; however, realizing a future where every experiment reliably feeds back into autonomous learning loops requires overcoming significant current barriers in data standardization and hardware interoperability.

Braga, Susana Santos; Santos, Nádia E.; Almeida‐Santos, Maria; Figueira, Flávio F.; Almeida Paz, Filipe A.

doi: 10.1002/med.70070pmid: 42288958

The present review describes the current knowledge on phosphonates designed for brain disease therapeutics, a less explored aspect of the studies on their medicinal chemistry. Because of their structural similarity with phosphates and of the ubiquitous presence of phosphate‐dependent processes in the brain, phosphonate compounds are able to influence brain chemistry, interfering with neurotransmission and phosphorous‐dependent bioprocesses. One of the main applications for phosphonates in the brain is Alzheimer's disease, for which they can be new drug candidates and/or afford innovative strategies for diagnostics. Such applications are described in the first section of this review, which includes a large number of reports on phosphonates with cholinesterase‐inhibiting activity, some recent studies exploring phosphonates for inhibiting the interaction between amyloid‐β protein and alcohol dehydrogenases, and phosphonate‐based materials used in proteomics‐based investigative and diagnosis platforms for the different stages of development of Alzheimer's disease. The second section of the review is dedicated to ischemic brain injury and to the development of phosphonates for active against NMDA and AMPA receptors with the purpose of reducing brain damage caused by glutamate excitotoxicity. Furthermore, agonists targeting the mGlu‐4 receptor suggest potential for promoting neuroregeneration. The review concludes by emphasizing the relevance of phosphonate stability, versatility, and ability to mimic natural phosphate groups in the development of new therapeutic agents for brain disorders, weighing the advantages against the gaps in knowledge in order to set future directions of research in brain health.