Synthesis and pharmacological characterization of multiply substituted 2H-chromene derivatives as P2Y6 receptor antagonists

Jung, Young‐Hwan; Shah, Qasim; Lewicki, Sarah A.; Pramanik, Asmita; Gopinatth, Varun; Pelletier, Julie; Sévigny, Jean; Iqbal, Jamshed

doi:10.1016/j.bmcl.2022.128981

Cited by 9 publications

(1 citation statement)

References 29 publications

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“…Among them, diisothiocyanate derivative MRS2578, which was developed by Jacobson’s group, exhibited potent inhibitory activity against P2Y 6 R (IC 50 = 37 nM) . Although MRS2578 displayed promising therapy effects in the DSS-induced colitis model, the irreversible binding, limited stability in aqueous solution, and limited effectiveness in vivo have prevented its use in clinical practice. , TIM-38 with a novel 2H-chromene scaffold (IC 50 = 4.3 μM) was identified in 2017, and then Jacobson’s group developed a series of TIM-38 derivatives in 2021 and 2022, , but none reached the magnitude of activity of MRS2578. Considering the unsolved crystal structure of P2Y 6 R, the lack of possible key residues on the P2Y 6 R binding site and high-throughput screening methods make it challenging to develop promising small-molecule antagonists targeting P2Y 6 R.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Selective P2Y₆R Antagonists with High Affinity and In Vivo Efficacy for Inflammatory Disease Therapy

et al. 2023

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As a member of purinoceptors, the P2Y 6 receptor (P2Y 6 R) plays a crucial role in modulating immune signals and has been considered as a potential therapeutic target for inflammatory diseases. On the basis of the speculated probable conformation and binding determinants of P2Y 6 R, a hierarchical strategy that combines virtual screening, bioassays, and chemical optimization was presented. A potent P2Y 6 R antagonist (compound 50) was identified to possess excellent antagonistic activity (IC 50 = 5.914 nM) and high selectivity. In addition, binding assays and chemical pull-down experiments confirmed that compound 50 was nicely bound to P2Y 6 R. Notably, compound 50 could effectively ameliorate DSS-induced ulcerative colitis in mice through inhibiting the activation of NLRP3 inflammasome in colon tissues. Moreover, treatment with compound 50 reduced LPS-induced pulmonary edema and infiltration of inflammatory cells in mice. These findings suggest that compound 50 could serve as a specific P2Y 6 R antagonist for treating inflammatory diseases and deserve further optimization studies.

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Section: Introductionmentioning

confidence: 99%

Discovery of Selective P2Y₆R Antagonists with High Affinity and In Vivo Efficacy for Inflammatory Disease Therapy

et al. 2023

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Silica Sulphuric Acid Catalyzed Intra‐Molecular Alkyne Carbonyl Metathesis (ACM): A Rapid Access to 2H‐Chromenes

Kumar Maurya,

Kumar,

Dey

et al. 2024

Asian J Org Chem

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A highly efficient, convenient and ecofriendly approach to access highly functionalized 2H‐chromenes via intramolecular aldehyde alkyne metathesis reaction was established starting from readily accessible alkyne‐tethered 2‐((3‐phenylprop‐2‐yn‐1‐yl) oxy)benzaldehydes and catalyzed by silica sulfuric acid (SiO2‐OSO3H, SSA) coupled with microwave irradiation. This reaction was well tolerated for a variety of substituents including different functional groups and it furnished the desired highly functionalized 2H‐chromene derivatives in good to excellent yields in a very short time. A systematic study of the conventional heating approach and microwave irradiation was performed to demonstrate the advantages of the microwave‐assisted condition in terms of high yield and shorter reaction time.

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Machine learning-aided search for ligands of P2Y6 and other P2Y receptors

Puhl,

Lewicki,

Gao

et al. 2024

Purinergic Signalling

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The P2Y6 receptor, activated by uridine diphosphate (UDP), is a target for antagonists in inflammatory, neurodegenerative, and metabolic disorders, yet few potent and selective antagonists are known to date. This prompted us to use machine learning as a novel approach to aid ligand discovery, with pharmacological evaluation at three P2YR subtypes: initially P2Y6 and subsequently P2Y1 and P2Y14. Relying on extensive published data for P2Y6R agonists, we generated and validated an array of classification machine learning model using the algorithms deep learning (DL), adaboost classifier (ada), Bernoulli NB (bnb), k-nearest neighbors (kNN) classifier, logistic regression (lreg), random forest classifier (rf), support vector classification (SVC), and XGBoost (XGB) classifier models, and the common consensus was applied to molecular selection of 21 diverse structures. Compounds were screened using human P2Y6R-induced functional calcium transients in transfected 1321N1 astrocytoma cells and fluorescent binding inhibition at closely related hP2Y14R expressed in CHO cells. The hit compound ABBV-744, an experimental anticancer drug with a 6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine scaffold, had multifaceted interactions with the P2YR family: hP2Y6R inhibition in a non-surmountable fashion, suggesting that noncompetitive antagonism, and hP2Y1R enhancement, but not hP2Y14R binding inhibition. Other machine learning-selected compounds were either weak (experimental anti-asthmatic drug AZD5423 with a phenyl-1H-indazole scaffold) or inactive in inhibiting the hP2Y6R. Experimental drugs TAK-593 and GSK1070916 (100 µM) inhibited P2Y14R fluorescent binding by 50% and 38%, respectively, and all other compounds by < 20%. Thus, machine learning has led the way toward revealing previously unknown modulators of several P2YR subtypes that have varied effects.

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Synthesis and pharmacological characterization of multiply substituted 2H-chromene derivatives as P2Y6 receptor antagonists

Cited by 9 publications

References 29 publications

Discovery of Selective P2Y₆R Antagonists with High Affinity and In Vivo Efficacy for Inflammatory Disease Therapy

Discovery of Selective P2Y₆R Antagonists with High Affinity and In Vivo Efficacy for Inflammatory Disease Therapy

Silica Sulphuric Acid Catalyzed Intra‐Molecular Alkyne Carbonyl Metathesis (ACM): A Rapid Access to 2H‐Chromenes

Machine learning-aided search for ligands of P2Y6 and other P2Y receptors

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Synthesis and pharmacological characterization of multiply substituted 2H-chromene derivatives as P2Y6 receptor antagonists

Cited by 9 publications

References 29 publications

Discovery of Selective P2Y6R Antagonists with High Affinity and In Vivo Efficacy for Inflammatory Disease Therapy

Discovery of Selective P2Y6R Antagonists with High Affinity and In Vivo Efficacy for Inflammatory Disease Therapy

Silica Sulphuric Acid Catalyzed Intra‐Molecular Alkyne Carbonyl Metathesis (ACM): A Rapid Access to 2H‐Chromenes

Machine learning-aided search for ligands of P2Y6 and other P2Y receptors

Contact Info

Product

Resources

About

Discovery of Selective P2Y₆R Antagonists with High Affinity and In Vivo Efficacy for Inflammatory Disease Therapy

Discovery of Selective P2Y₆R Antagonists with High Affinity and In Vivo Efficacy for Inflammatory Disease Therapy