Jan 2026· Journal of Medicinal Chemistry· Vol 69, pp. 1507-1529· 1 citation· 41 references
Medicine
TL;DR
D8, which contained 2-oxo-tetrahydroquinoline by carbonyl migration form B53, manifests an excellent SGRM with remarkable transrepression potency and optimized binding mode within the GR LBD, underscoring its therapeutic potential and validating the design strategy.
Abstract
Glucocorticoids (GCs) are limited by severe side effects, driving the development of selective glucocorticoid receptor modulators (SGRMs) with improved therapeutic profiles. We previously development the SGRM lead B53, which suffered from poor metabolic stability. In this study, structure-guided optimization of B53 yielded 43 novel sulfonamide derivatives. Among them, D8, which contained 2-oxo-tetrahydroquinoline by carbonyl migration form B53, manifests an excellent SGRM with remarkable transrepression potency (IC50NF-κB = 0.9 nM) superior to dexamethasone (IC50 NF-κB = 5.0 nM). Besides, D8 exhibits a significantly higher specificity for GR over AR, MR, and PR and exhibited less adverse effects on osteoprotegerin. Furthermore, D8 demonstrated improved metabolic stability and optimized binding mode within the GR LBD. In vivo, oral administration of D8 significantly alleviated dermatitis and autoimmune hepatitis in mouse models, underscoring its therapeutic potential and validating our design strategy.
Compound 9u exhibited significant antiproliferative activity in MTAP-deleted HCT116 cancer cells, with an IC50 value of 13 nM, exhibiting 70-fold selectivity over MTAP wild type HCT116 cells, and 9u displayed robust efficacy across diverse MTAP-deleted cancer cell lines, achieving IC50 values of <1.5-51 nM.
Bing Liu, Shao-Yan Li, Hui Shi et al.· Bioorganic chemistry (Print)· 0 citations
In this study, new imidazo[1,2-a]pyrazine derivative 15 (YS3074) and pyrazine derivative 17 (YS3375) are identified and optimized as potent and selective ENPP1 inhibitors. Compounds 15 and 17 both exhibited high potency and selectivity toward ENPP1 (IC50 = 4.23 nM and 19.4 nM, respectively) with negligible ENPP2 inhibition (>10 μM) and weak ENPP3 inhibition (>3 μM). Both enhanced cGAMP-induced expression of STING pathway genes (IFNB1, CXCL10, IL6) in a concentration-dependent manner without cytotoxicity, producing stronger and more sustained activation than MV-658. This effect, dependent on the cGAMP-STING axis, was attributed to inhibition of ENPP1-mediated cGAMP hydrolysis. Additionally, compounds 15 and 17 showed no inhibition of the hERG channel (IC50 > 30 μM), indicating a favorable cardiac safety profile. In the CT-26 colorectal cancer model, compounds 15 and 17, administered at 40 mg/kg in combination with an anti-PD-1 antibody, achieved superior tumor growth inhibition (TGI: 73% and 67%, respectively), significantly prolonged survival, and were well tolerated with no observable body weight loss. These results establish 15 and 17 as promising ENPP1 inhibitors with favorable safety profiles, supporting their potential in combination cancer immunotherapy.
Zhiyue He, Ying-Ying Zhang, Shi-Ping Zhan et al.· European journal of medicina...· 0 citations
Acute pancreatitis (AP) is a common, serious, pancreatic inflammation representing an unmet therapeutical need. Here, we report the design and synthesis of a series of compounds as dual 5-lipoxygenase (LOX)/soluble epoxide hydrolase (sEH) inhibitors aimed at favorably modulating inflammatory lipid mediator pathways. The tetrahydroquinoline-based compound 11 emerged as the most promising candidate, showing potent in vitro inhibition of both enzymes and satisfactory metabolic stability. Compound 11 was evaluated in a cerulein-induced murine model of AP, where it significantly reduced pancreatic damage, cellular infiltration, and edema formation. These effects led to beneficial modulation of LMs and attenuation of ferroptosis, concomitant with activation of the Nrf2 antioxidant pathway and upregulation of cytoprotective markers. Compound 11 ameliorated lung, liver, and kidney secondary damage, displaying an improved in vivo pharmacokinetic profile. Overall, these findings reveal compound 11 as a promising anti-inflammatory agent supporting dual 5-LOX/sEH inhibition, coupled with Nrf2 activation, as a viable strategy for AP.
D. D’Avino, T. Ciaglia, P. M. Jordan et al.· Journal of Medicinal Chemist...· 0 citations
Alzheimer's disease (AD) is a neurodegenerative disorder with intricate pathogenic factors. Multi-target drug design offers a promising approach to address AD's complex pathogenesis. α-Mangostin (α-M), a natural product with multifunctional anti-AD potential, is limited by poor aqueous solubility and bioavailability. This work employed regioselective Williamson O-alkylation to semi-synthesize three novel α-M alkylamine derivatives (1-3), enabling tunable mono- and disubstitution. In silico predictions demonstrated that disubstituted compounds 2 and 3 exhibited markedly improved blood-brain barrier permeability and oral bioavailability. While experimental results showed that monosubstitution optimally balanced intrinsic antioxidant activity with target binding. Compound 1 displayed potent AChE inhibition (IC50 = 0.11 μM) with high selectivity (SI = 59.27), effectively inhibited both self-induced and AChE-induced Aβ aggregation (53.8% and 57.3%, respectively), and exhibited excellent antioxidant capacity (·OH IC50 = 0.19 μM). Meanwhile, disubstitution achieved superior BuChE inhibition by occupying both sides of the expanded active site pocket. Furthermore, 1 significantly reduced ROS levels by ~48% in C. elegans. These results highlight the potential of tunable α-M derivatives as promising anti-AD candidates.
Tropomyosin kinase B (TrkB) is an attractive target for cancer treatment and is emerging as a target for the treatment of neurological disorders, specifically epilepsy, due to its role in regulating neuronal degeneration and inflammation. However, current medications frequently suffer from toxicity, resistance, and poor metabolism. In the present study, four new series of tetrazole annulated benzopyridodiazepine derivatives (26 examples) were synthesized in two steps: intramolecular cyclization with various sets of amines to produce benzopyridodiazepinone derivatives, and then, in the second step, the tetrazole ring was introduced by the reaction of imidoyl chloride with azide. All four synthesized series were assessed for in vitro inhibitory activity against tropomyosin kinase (TrkB) using both enzyme and cellular assays. To further evaluate the biological efficacy of the synthesized derivatives, we conducted ROS measurements, fluorescence-based microscopy, and flow cytometry to determine the mode of action and the induction of apoptosis. Molecular docking, ADMET, and DFT studies supported the binding at the TrkB site and suggested favorable pharmacokinetic profiles. Overall, the results indicate that the synthesized compounds are highly promising candidates, especially 14h, which shows significant inhibition of TrkB in neuroblastoma cells. Thus, the tetrazole annulated benzopyridodiazepine is an interesting molecule for exploration in the management of cancer and neurological disorders.
Shivangi Jaiswal, K. Bhardwaj, Smita Jain et al.· RSC Advances· 0 citations
Findings suggested that compound 6m might be a potent candidate as a succinate dehydrogenase inhibitor (SDHI) against R. solani with strong protective and curative effects even at 50 μg/mL.
Bo Luo, Yan-Bing Wu, Qingsi Zhang et al.· Journal of Agricultural and...· 0 citations
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