Discovery and computational studies of 2-phenyl-benzoxazole acetamide derivatives as promising P2Y14R antagonists with anti-gout potential

Zhou, Mi; Wang, Weiwei; Wang, Zhongkui; Wang, Yilin; Zhu, Yifan; Lin, Zhiqian; Tian, Sheng; Huang, Yuan; Hu, Qinghua; Li, Huanqiu

doi:10.1016/j.ejmech.2021.113933

Cited by 14 publications

(22 citation statements)

References 50 publications

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“…In an effort to explore other scaffolds reported to be P2Y 14 R antagonists as potential lead compounds, in addition to the piperidine series of 1 , we considered recently reported antagonists 4a (Zhou et al) and 4b (Wang et al). , We resynthesized the uncharged, small molecular P2Y 14 R antagonist 4a in the 2-phenyl-benzoxazole acetamide series (Scheme S1, Supporting information, compound 46 in Zhou et al). We evaluated the compound in a whole cell (hP2Y 14 R-expressing CHO cells) binding assay using 52 (Supporting Information), a fluorescent analogue of 1 used in our previous studies .…”

Section: Resultsmentioning

confidence: 99%

“…Treatment of 39 (all residue from hydrolysis of 38, 0.057 mmol) by using Procedure C gave 17 (5.08 mg, 18%) as a mixture of two constitutional isomers (1:1): 1 H NMR (400 MHz, (18). Treatment of 47 (6 mg, 0.0112 mmol) by using Procedure A gave 18 (3 mg, overall yield 54% from 45): 1 H NMR (400 MHz, MeOD) δ 8.73 (s, 1H), 8.41 (d, J = 1.9 Hz, 1H), 8.06− 7.95 (m, 4H), 7.92 (dd, J = 8.9, 2.0 Hz, 1H), 7. thoic Acid (20) (25). Procedure E. A mixture of 1,4dibromobenzene (2.9 g, 12.5 mmol) and magnesium turnings (60.8 mg, 2.5 mmol) in THF (5 mL) was sonicated for 2 h. The solution was cooled to 0 °C.…”

Section: -(4-(azepan-4-yl)phenyl)-7-(4-(trifluoromethyl)phenyl)-2-nap...mentioning

confidence: 99%

“…Other chemotypes have been reported to be P2Y 14 R antagonists, including the 2-phenyl-benzoxazole acetamide derivative 4a and 5-amide-1H-pyrazole-3-carboxyl derivative 4b. 20,21 Here, we have varied the ring size of the alicyclic amine of 1 from four to eight atoms, with bridging and functional group substitution, including spiro and fused cyclo(aza)aliphatic rings. The occurrence, conformation, and utility of various cycloalkyl rings in experimental drugs have been reviewed.…”

Section: ■ Introductionmentioning

confidence: 99%

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Alicyclic Ring Size Variation of 4-Phenyl-2-naphthoic Acid Derivatives as P2Y₁₄ Receptor Antagonists

et al. 2023

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P2Y14 receptor (P2Y14R) is activated by extracellular UDP-glucose, a damage-associated molecular pattern that promotes inflammation in the kidney, lung, fat tissue, and elsewhere. Thus, selective P2Y14R antagonists are potentially useful for inflammatory and metabolic diseases. The piperidine ring size of potent, competitive P2Y14R antagonist (4-phenyl-2-naphthoic acid derivative) PPTN 1 was varied from 4- to 8-membered rings, with bridging/functional substitution. Conformationally and sterically modified isosteres included N-containing spirocyclic (6–9), fused (11–13), and bridged (14, 15) or large (16–20) ring systems, either saturated or containing alkene or hydroxy/methoxy groups. The alicyclic amines displayed structural preference. An α-hydroxyl group increased the affinity of 4-(4-((1R,5S,6r)-6-hydroxy-3-azabicyclo[3.1.1]heptan-6-yl)phenyl)-7-(4-(trifluoromethyl)phenyl)-2-naphthoic acid 15 (MRS4833) compared to 14 by 89-fold. 15 but not its double prodrug 50 reduced airway eosinophilia in a protease-mediated asthma model, and orally administered 15 and prodrugs reversed chronic neuropathic pain (mouse CCI model). Thus, we identified novel drug leads having in vivo efficacy.

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Section: Resultsmentioning

confidence: 99%

Section: -(4-(azepan-4-yl)phenyl)-7-(4-(trifluoromethyl)phenyl)-2-nap...mentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Alicyclic Ring Size Variation of 4-Phenyl-2-naphthoic Acid Derivatives as P2Y₁₄ Receptor Antagonists

et al. 2023

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“…It was demonstrated that compound 8, exhibited the good antagonistic activity against P2Y 14 R, could restrain MSU-induced pyroptosis of THP-1 cells through blocking the activation of NLRP3 inflammasome ( 106 ). In another study, 2-phenyl-benzoxazole acetamide derivative (compound 52) showed a strong inhibitory effect on paw swelling and inflammatory cell infiltration through cAMP/NLRP3/GSDMD signaling pathways in MSU-induced GA mice ( 107 ). In a recent study, Lu et al.…”

Section: Therapeutic Strategies For Targeting Nlrp3 In Gamentioning

confidence: 99%

Role of NLRP3 in the pathogenesis and treatment of gout arthritis

Liu

Wang

2023

Front. Immunol.

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Gout arthritis (GA) is a common and curable type of inflammatory arthritis that has been attributed to a combination of genetic, environmental and metabolic factors. Chronic deposition of monosodium urate (MSU) crystals in articular and periarticular spaces as well as subsequent activation of innate immune system in the condition of persistent hyperuricemia are the core mechanisms of GA. As is well known, drugs for GA therapy primarily consists of rapidly acting anti-inflammatory agents and life-long uric acid lowering agents, and their therapeutic outcomes are far from satisfactory. Although MSU crystals in articular cartilage detected by arthrosonography or in synovial fluid found by polarization microscopy are conclusive proofs for GA, the exact molecular mechanism of NLRP3 inflammasome activation in the course of GA still remains mysterious, severely restricting the early diagnosis and therapy of GA. On the one hand, the activation of Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome requires nuclear factor kappa B (NF-κB)-dependent transcriptional enhancement of NLRP3, precursor (pro)-caspase-1 and pro-IL-1β, as well as the assembly of NLRP3 inflammasome complex and sustained release of inflammatory mediators and cytokines such as IL-1β, IL-18 and caspase-1. On the other hand, NLRP3 inflammasome activated by MSU crystals is particularly relevant to the initiation and progression of GA, and thus may represent a prospective diagnostic biomarker and therapeutic target. As a result, pharmacological inhibition of the assembly and activation of NLRP3 inflammasome may also be a promising avenue for GA therapy. Herein, we first introduced the functional role of NLRP3 inflammasome activation and relevant biological mechanisms in GA based on currently available evidence. Then, we systematically reviewed therapeutic strategies for targeting NLRP3 by potentially effective agents such as natural products, novel compounds and noncoding RNAs (ncRNAs) in the treatment of MSU-induced GA mouse models. In conclusion, our present review may have significant implications for the pathogenesis, diagnosis and therapy of GA.

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“…Furthermore, AChE inhibitor 6 ( Macedo Vaz et al, 2022 ) for treatment of Alzheimer’s disease and Mtb RNAP inhibitor 7 ( Mekonnen Sanka et al, 2022 ) for antitubercular and antimicrobial treatment were deserve further study. Moreover, a lead compound 8 of DDP4 inhibitor ( Maslov et al, 2022 ) and acetamide derivative 9 ( Zhou et al, 2022 ) as P2Y14R antagonist were considered as drug candidates for treating type 2 diabetes and gout, respectively. Additionally, potential SARS-CoV-2 main protease inhibitor 10 ( Dong et al, 2023 ) and carbazole alkaloids from Murraya koenigii ( Wadanambi et al, 2023 ) were identified as a promising drug candidates for inhibiting coronavirus infection.…”

Section: Computational Chemistry In Drug Discoverymentioning

confidence: 99%

Recent updates in click and computational chemistry for drug discovery and development

et al. 2023

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Drug discovery is a costly and time-consuming process with a very high failure rate. Recently, click chemistry and computer-aided drug design (CADD) represent popular areas for new drug development. Herein, we summarized the recent updates in click and computational chemistry for drug discovery and development including clicking to effectively synthesize druggable candidates, synthesis and modification of natural products, targeted delivery systems, and computer-aided drug discovery for target identification, seeking out and optimizing lead compounds, ADMET prediction as well as compounds synthesis, hopefully, inspires new ideas for novel drug development in the future.

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Discovery and computational studies of 2-phenyl-benzoxazole acetamide derivatives as promising P2Y14R antagonists with anti-gout potential

Cited by 14 publications

References 50 publications

Alicyclic Ring Size Variation of 4-Phenyl-2-naphthoic Acid Derivatives as P2Y₁₄ Receptor Antagonists

Alicyclic Ring Size Variation of 4-Phenyl-2-naphthoic Acid Derivatives as P2Y₁₄ Receptor Antagonists

Role of NLRP3 in the pathogenesis and treatment of gout arthritis

Recent updates in click and computational chemistry for drug discovery and development

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Discovery and computational studies of 2-phenyl-benzoxazole acetamide derivatives as promising P2Y14R antagonists with anti-gout potential

Cited by 14 publications

References 50 publications

Alicyclic Ring Size Variation of 4-Phenyl-2-naphthoic Acid Derivatives as P2Y14 Receptor Antagonists

Alicyclic Ring Size Variation of 4-Phenyl-2-naphthoic Acid Derivatives as P2Y14 Receptor Antagonists

Role of NLRP3 in the pathogenesis and treatment of gout arthritis

Recent updates in click and computational chemistry for drug discovery and development

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Product

Resources

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Alicyclic Ring Size Variation of 4-Phenyl-2-naphthoic Acid Derivatives as P2Y₁₄ Receptor Antagonists

Alicyclic Ring Size Variation of 4-Phenyl-2-naphthoic Acid Derivatives as P2Y₁₄ Receptor Antagonists