Journal of Medicinal Chemistry

Benzylguanidine, a norepinephrine analogue with high NET affinity, serves as a promising scaffold for visualizing cardiac sympathetic function. This study investigated whether ¹⁸F-labeled benzylguanidine derivatives with systematical <i>meta</i>-halogen substitution could be optimized for PET imaging of cardiac sympathetic innervation. Five derivatives were radiolabeled efficiently wit…

Safety concerns associated with the release of a tiny amount of gadolinium (Gd³⁺) from clinically used gadolinium-based contrast agents (GBCAs) underscore the need for ultrastable alternatives for magnetic resonance imaging (MRI). Here we report <b>Gd-L2</b>, a fully alkyl-substituted, chiral Gd-DOTA derivative incorporating a tetraethyl-substituted cyclen backbone and α-arm methyl gro…

Hepatitis B surface antigen (HBsAg) is overproduced in chronic HBV infection, causing immune tolerance and hindering a functional cure. The first HBsAg production inhibitor RG7834 demonstrated potent anti-HBV activity and advanced to Phase I clinical trials but was discontinued due to neurotoxicity concerns. Systematic structure optimization was performed based on RG7834, ultimately leading to th…

Thioredoxin reductase (TrxR) overexpression in tumors is a marker of poor prognosis for liver cancer. Current TrxR inhibitors primarily feature a single pharmacophore. However, dual-pharmacophore TrxR inhibitors have been rarely reported, lacking a clear report on the relationship between their antitumor and potential regulation of tumor immune microenvironment (TIME). Here, we developed a series…

PD-1/PD-L1 and VEGF pathways jointly mediate T-cell dysfunction and immune suppression, limiting the efficacy of immune checkpoint inhibitors. We developed an ⁸⁹Zr-labeled bispecific immuno-PET probe, ⁸⁹Zr-JS207, for noninvasive imaging of PD-1 and VEGF in tumors. ⁸⁹Zr-JS207 was prepared via <i>p</i>-isothiocyanatobenzyl-desferrioxamine (<i>p</i>-NCS-Bz-DFO) conju…

In cancers with <i>MTAP</i> deletions, MAT2A inhibition has emerged as a promising therapeutic strategy in cancer treatment through a synthetic mechanism. Herein, we report the design and optimization of a novel series of pyridazinone-based MAT2A inhibitors via a ring-opening strategy from <b>AGI-41998</b>. Through iterative structure-activity relationship (SAR) studies, compound <b>33</b> was id…

The eleven-nineteen leukemia protein (ENL), a YEATS domain-containing acyl-lysine reader, represents a critical dependency in acute myeloid leukemia (AML). We previously reported our first-generation ENL proteolysis-targeting chimera (PROTAC) degrader, MS41. Here, via a comprehensive structure-activity relationship (SAR) study, we discovered MS108 (compound <b>124</b>), the most potent ENL degrad…

Colony-stimulating factor 1 receptor (CSF1R) is a key regulator of macrophage-driven liver inflammation. Here, we report a series of CSF1R inhibitors discovered through a structure-guided optimization strategy for the acute-phase treatment of acetaminophen-induced liver injury. For instance, compound <b>C52</b> exhibited potent CSF1R inhibition, a kinome-wide selective profile, and low cellular c…

Squaramides (SQA) were reported as potent antituberculosis drugs through inhibition of the mycobacterial enzyme adenosine triphosphate (ATP) synthase, which is critical for ATP synthesis. However, squaramide compounds showed high metabolic clearance (CL) despite their promising potency and selectivity. Herein, we describe lead optimization efforts to improve the potency and metabolic stability of…

The structural diversity of natural products provides a major source for discovering antimicrobials with novel structures or mechanisms to overcome microbial resistance. Herein, we prepared a series of rutaecarpine-pyridinium quaternary ammonium conjugates by using rutaecarpine as the lead compound. Bioactivity evaluation demonstrated that <b>5dl</b> exhibits outstanding antibacterial activity ag…

Guided by the pharmacophore-oriented molecular generation platform PhoreGen, we employed rilpivirine (RPV) as a lead compound to generate 300 structurally diverse analogs that preserve key pharmacophoric features. Subsequent drug-likeness evaluation, molecular docking score, and synthetic feasibility led to the identification of compound <b>No.102</b> (<b>A19</b>), which displayed potent inhibiti…

Targeted protein degradation can be induced by recruiting a protein of interest to an E3 ligase, resulting in its ubiquitination and subsequent proteasome-mediated degradation. However, only a small number of E3 ligases have been utilized for degradation. Expansion of the repertoire of useful E3 ligases via the identification of ligands to those ligases could broaden the scope and applicability o…

Herein, we described the design and synthesis of a series of melampomagnolide B-dithiocarbamate hybrids and the evaluation of their anti-lung cancer activities. The most active compound <b>86</b> (IC₅₀ = 0.46 μM) exhibited a highly potent inhibitory effect on NCI-H820 cells, with a 44-fold increase compared to the natural product melampomagnolide B (IC₅₀ = 20.43 μM). Compoun…

Genetic mutations in the leucine-rich repeat kinase 2 (LRRK2) protein have been linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder for which treatments are limited. Herein, we describe the invention of a macrocyclic LRRK2 inhibitor lead chemical series. Rigorous application of knowledge-, structure-, and property-based drug design culminated in the discover…