Novel Pyrazolo[4,3-<i>d</i>]pyrimidine as Potent and Orally Active Inducible Nitric Oxide Synthase (iNOS) Dimerization Inhibitor with Efficacy in Rheumatoid Arthritis Mouse Model

Shi, Jing; Chen, Liu Zeng; Wang, Bao Shi; Huang, Xin; Jiao, Ming; Liu, Ming Ming; Tang, Wen; Liu, Xin Hua

doi:10.1021/acs.jmedchem.9b00039

Cited by 33 publications

(16 citation statements)

References 38 publications

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“…Nitric oxide (NO) is produced by mammalian cells through metabolism of l -arginine and plays an important role in regulating inflammation and immune responses 13 . NO is a key pro-inflammatory mediator and excessive production of NO was proved to be associated with many inflammatory diseases 12 , 14 . Thus, it is an established view that compounds inhibiting the production of NO may offer potential opportunity to treat inflammatory diseases.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and in vitro and in vivo anti-inflammatory activity of novel 4-ferrocenylchroman-2-one derivatives

Guo

Chen

Shen

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of novel 4-ferrocenylchroman-2-one derivatives were designed and synthesised to discover potent anti-inflammatory agents for treatment of arthritis. All the target compounds had been screened for their anti-inflammatory activity by evaluating the inhibition effect of LPS-induced NO production in RAW 264.7 macrophages. Among them, 4-ferrocenyl-3,4-dihydro-2H-benzo[g]chromen-2-one (3h) was found to be the most potent compound in inhibiting the productions of NO with low toxicity. This compound also exhibited significant inhibition of the productions of IL-6 and TNF-α in RAW 264.7 macrophages. Preliminary mechanism studies indicated that compound 3h could inhibit the activation of LPS-induced NF-κB and MAPKs signalling pathways. The in vivo anti-inflammatory effect of this compound was determined in the rat adjuvant-induced arthritis model.

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Section: Resultsmentioning

confidence: 99%

Synthesis and in vitro and in vivo anti-inflammatory activity of novel 4-ferrocenylchroman-2-one derivatives

Guo

Chen

Shen

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Considering again the contribution of 3,4,5‐trimethoxyphenyl moiety to anti‐inflammatory activity, a fourth series of compounds 218 was designed and synthesized by introducing a trimethoxystyryl group at C‐5 of pyrazolo[4,3‐ d ]pyrimidine nucleus. Out of this series, the compound having propyl‐2‐amine group at R 1 218 significantly inhibited NO (90.4% at 10 µM concentration), iNOS (IC 50 1.12 µM), and iNOS dimerization …”

Section: Synthetic Inos Inhibitorsmentioning

confidence: 98%

“…3,4,5‐Trimethoxyphenyl moiety is another important structural component for anti‐inflammatory potential of molecules . Based on this know‐how, Shi et al designed and synthesized a series of 3,4,5‐trimethoxyphenyl‐pyrazolo[4,3‐ d ]pyrimidine analogs 215 as anti‐inflammatory agents and iNOS inhibitors. However, these derivatives did not display any significant activity.…”

Section: Synthetic Inos Inhibitorsmentioning

confidence: 99%

Inducible nitric oxide synthase inhibitors: A comprehensive update

Minhas

Bansal

2019

Medicinal Research Reviews

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Inducible nitric oxide synthase (iNOS), which is expressed in response to bacterial/proinflammatory stimuli, generates nitric oxide (NO) that provides cytoprotection. Overexpression of iNOS increases the levels of NO, and this increased NO level is implicated in pathophysiology of complex multifactorial diseases like Parkinson's disease, Alzheimer's disease, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Selective inhibition of iNOS is an effective approach in treatment of such complex diseases. L-Arginine, being a substrate for iNOS, is the natural lead to develop iNOS inhibitors. More than 200 research reports on development of nitric oxide synthase inhibitors by different research groups across the globe have appeared in literature so far. The first review on iNOS, in 2002, discussed the iNOS inhibitors under two classes that is, amino acid and non-amino acid derivatives. Other review articles discussing specific chemical classes of iNOS inhibitors also appeared during last decade. In the present review, all reports on both natural and synthetic iNOS inhibitors, published 2002 onwards, are studied, classified, and discussed to provide comprehensive information on iNOS inhibitors. The synthetic inhibitors are broadly classified into two categories that is, arginine and non-arginine analogs. The latter are further classified into amidines, five-or six-membered heterocyclics, fused cyclics, steroidal type, and chalcones analogs. Structures of the most/significantly potent compounds from each report are provided to know the functional groups important for incurring iNOS inhibitory activity and selectivity. This review is aimed to provide a comprehensive view to the medicinal chemists for rational designing of novel and potent iNOS inhibitors. K E Y W O R D S arginine, inflammation, inhibitors, multifactorial disease, nitric oxide 1 | INTRODUCTION Nitric oxide (NO) is a relaxing factor derived from endothelium, which is responsible for neuronal transmission, cardiovascular, gastrointestinal, genitourinary, respiratory, antipathogenic, and antitumor responses. The production of NO is effected by nitric oxide synthase (NOS) through catalysis of NADPH-dependent oxidation of L-arginine (the substrate). 1NOS exists in three distinct isoforms, depending on the site of its existence that is, neuronal NOS (nNOS, type I), inducible or inflammatory NOS (iNOS, type II) and endothelial NOS (eNOS, type III). Constitutive NOS are regulated by the binding of calcium-calmodulin protein, whereas iNOS is transcriptionally regulated and calcium-calmodulin independent. NO plays both physiological and pathological roles depending on the magnitude and duration of its production. 2 The physiological roles of NO are executed by soluble guanylate cyclase. Indeed, NO activates it, with the consequent increase of cyclic guanosine-3′,5′-monophosphate (cGMP) level, which subsequently activates intracellular effector molecules, cGMPdependent protein kinases, cGMP-gated ion channels, and cGMP-regulated phosphodiesteras...

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“…The results revealed that the administration of the compound (125) caused a noteworthy suppression to hind paw swelling on day 30, which was comparable to the effect noticed in the aspirinexposed group. 118 The potency of the selected pyrimidine derivatives versus inammatory mediator (NO) is provided in Table SI…”

Section: Inhibition Of Nitric Oxide (No) Generationmentioning

confidence: 99%

Research developments in the syntheses, anti-inflammatory activities and structure–activity relationships of pyrimidines

et al. 2021

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Novel Pyrazolo[4,3-d]pyrimidine as Potent and Orally Active Inducible Nitric Oxide Synthase (iNOS) Dimerization Inhibitor with Efficacy in Rheumatoid Arthritis Mouse Model

Cited by 33 publications

References 38 publications

Synthesis and in vitro and in vivo anti-inflammatory activity of novel 4-ferrocenylchroman-2-one derivatives

Synthesis and in vitro and in vivo anti-inflammatory activity of novel 4-ferrocenylchroman-2-one derivatives

Inducible nitric oxide synthase inhibitors: A comprehensive update

Research developments in the syntheses, anti-inflammatory activities and structure–activity relationships of pyrimidines

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