Synthesis of new 1‐phenylthieno[1,2,4]triazolo[4,3‐<i>a</i>]pyrimidin‐5(4<i>H</i>)‐one derivatives

Song, Yang-Heon; Son, Hoon Young

doi:10.1002/jhet.549

Cited by 15 publications

(5 citation statements)

References 23 publications

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“…Aminothiophene 87 was converted into the thiourea derivative 88 using amino thiocyanate and benzoyl chloride before refluxing in ethanolic KOH gave the desired thiopyrimidinone intermediates 89 and 90 . 26 Finally, the last thiopyrimidinone building block 94 was synthesized in a three-step sequence, whereby 2-amino-5- fluorobenzoic acid 91 was converted into the thiourea derivative 92 by using ethoxycarbonyl isothiocyanate under refluxing conditions, activation of the acid with acetic anhydride enabled nucleophilic attack and closure of the thiopyrimidinone ring to give 93 , and removal of the ethyl carbamate under basic conditions resulted in the isolation of 94 in good yield.…”

Section: Resultsmentioning

confidence: 99%

Development of matrix metalloproteinase-13 inhibitors – A structure-activity/structure-property relationship study

Fuerst

Choi

Knapinska

et al. 2018

Bioorganic & Medicinal Chemistry

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A structure-activity/structure-property relationship study based on the physicochemical as well as in vitro pharmacokinetic properties of a first generation matrix metalloproteinase (MMP)-13 inhibitor (2) was undertaken. After systematic variation of inhibitor 2, compound 31 was identified which exhibited microsomal half-life higher than 20 min, kinetic solubility higher than 20 μM, and a permeability coefficient greater than 20 × 10 cm/s. Compound 31 also showed excellent in vivo PK properties after IV dosing (C = 56.8 μM, T (plasma) = 3.0 h, Cl = 0.23 mL/min/kg) and thus is a suitable candidate for in vivo efficacy studies in an OA animal model.

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Section: Resultsmentioning

confidence: 99%

Development of matrix metalloproteinase-13 inhibitors – A structure-activity/structure-property relationship study

Fuerst

Choi

Knapinska

et al. 2018

Bioorganic & Medicinal Chemistry

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“…7A) to selectively recognize compounds of individual chemotypes. For this, we assembled a larger library containing 113 AstraZeneca and related allosteric CCR2 antagonists (AZ [120][121][122][123] ), 52 UCB Pharma antagonists [119,124], 93 Johnson & Johnson antagonists (JNJ, [125][126][127]), and 79 GlaxoSmithKline antagonists (GSK [128]) from literature, as well as 50 published [129] and patented [130] BMS compounds, and 40 patented ChemoCentryx (CCX) compounds [131][132][133]. The 5t1a pocket was then challenged with recognizing active compounds of individual chemotypes against inactives (from all chemotypes) and the original set of 2950 decoys.…”

Section: Ccr2 Allosteric Pocket Conformations Are Antagonist-chemotyp...mentioning

confidence: 99%

Molecular determinants of antagonist interactions with chemokine receptors CCR2 and CCR5

Dawson,

Wadman,

Zhang

et al. 2023

Preprint

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By driving monocyte chemotaxis, the chemokine receptor CCR2 shapes inflammatory responses and the formation of tumor microenvironments. This makes it a promising target in inflammation and immuno-oncology. Unfortunately, despite extensive efforts, no CCR2-targeting therapeutics have yet reached the clinic. Cited reasons include the redundancy of the chemokine system, suboptimal properties of compound candidates, and poor agreement of clinical responses with preclinical murine model studies.Structure-based drug design approaches can rationalize and greatly accelerate CCR2 compound discovery and optimization. The prerequisites for such efforts include a good atomic-level understanding of the molecular determinants of action of existing antagonists.In this study, using molecular docking and artificial-intelligence-powered compound library screening, we uncover the structural principles of small molecule antagonism and selectivity towards CCR2 and its sister receptor CCR5. We show that CCR2 orthosteric inhibitors universally occupy an inactive-state-specific tunnel between receptor helices 1 and 7; we also discover an unexpected role for an extra-helical groove accessible through this tunnel, suggesting its potential as a new targetable interface for CCR2 and CCR5 modulation. We implicate a single CCR2 residue, S1012.63, as a determinant of CCR2/CCR5 and human/mouse antagonist selectivity, and corroborate its role through experimental gain-of-function mutagenesis. We systematically identify the binding determinants for various chemotypes of allosteric antagonists. We establish a critical role of induced fit in antagonist recognition, reveal strong chemotype selectivity of existing structures, and demonstrate the high predictive potential of a new deep-learning-based compound scoring function. Finally, we expand the available CCR2 structural landscape with computationally generated chemotype-specific models well-suited for structure-based antagonist design.

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“…The inhibitory activities of synthesized [2,3-d]thienopyrimidine derivatives 6Aa-g and [3,2-d]thienopyrimidine derivatives 6Ba-d against STAT3 activation by IL-6 were evaluated according to the reported method [25]. In brief, Hep3B cells that had been stably transformed with the pStat3-Luc plasmid were stimulated with IL-6 (10 ng/ml) for 12 h in the presence or absence of compounds 6Aa-g and 6Ba-d.…”

Section: Il-6-induced Stat3-dependent Promoter Activitymentioning

confidence: 99%

“…Phosphorylation of STAT3 at Y705 is mediated not only by the gp130/Jak pathway but also EGFR, which enhances immune response and cell proliferation without feedback from suppressors of cytokine signaling 3 (SOCS3), a negative regulator [22]. For that reason, we have designed and synthesized heterocyclic derivatives related to thienopyrimidines as potent STAT3 inhibitors [23][24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Thienopyrimidine Derivatives as Inhibitors of STAT3

Jang

Kim

Rho

et al. 2019

Journal of Microbiology and Biotechnology

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A series of thienopyrimidine compounds (6Aa-g and 6Ba-d) were synthesized and characterized by NMR spectroscopy and mass spectrometry. These compounds (6Aa-g and 6Ba-d) potently inhibited STAT3 expression induced by IL-6 in a dose-dependent manner with IC 5 0 values of 5.73-0.32 µM. Among the prepared thienopyrimidine derivatives, 6Aa, 6Ab, 6Ba and 6Bc significantly suppressed the phosphorylation of STAT3 and ERK1/2 stimulated by IL-6 in Hep3B cells. Furthermore, the synthesized compounds might be useful remedies for the treatment of inflammatory diseases by inhibiting the action of IL-6.

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Synthesis of new 1‐phenylthieno[1,2,4]triazolo[4,3‐a]pyrimidin‐5(4H)‐one derivatives

Abstract: A series of novel 1-phenylthieno[1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-one derivatives 5 and 6 were synthesized by oxidative cyclization of thienopyrimidinonyl hydrazones using iodobenzene diacetate.

Cited by 15 publications

References 23 publications

Development of matrix metalloproteinase-13 inhibitors – A structure-activity/structure-property relationship study

Development of matrix metalloproteinase-13 inhibitors – A structure-activity/structure-property relationship study

Molecular determinants of antagonist interactions with chemokine receptors CCR2 and CCR5

Synthesis of Thienopyrimidine Derivatives as Inhibitors of STAT3

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